Chemokine receptor antagonists

ABSTRACT

A compound of formula (I) or a pharmaceutically acceptable salt or prodrug ester thereof: 
     
       
         
         
             
             
         
       
     
     wherein the variants R, R9, Z, X, Q and Y are defined in the specification.

The invention relates to bicyclic carbonyl amino derivatives which areantagonists of Chemokine Receptor 2 (CCR-2) and Chemokine Receptor 5(CCR-5), and to their use in the treatment of diseases and disorderswhich involve migration and activation of monocytes and T-cells,including inflammatory diseases.

Accordingly the invention in a first aspect provides a compound offormula (I), or a pharmaceutically acceptable salt or prodrug esterthereof:

Wherein: Z is CR₁R₂, NR₃, O or S;

R is selected from the group consisting of hydroxy, an optionallysubstituted C₁-C₇ alkoxy, C₂-C₇ alkenoxy, cycloalkyloxy, aryloxy,heteroaryloxy, aryl-C₁-C₇ alkoxy or heteroaryl-C₁-C₇ alkoxy, anoptionally substituted C₁-C₇ alkyl or C₂-C₇ alkenyl, an optionallysubstituted aryl, heteroaryl or an optionally substituted aryl-C₁-C₇alkyl group;R9 represents one or more ring substituents selected from the groupconsisting of H, hydroxy, an optionally substituted C₁-C₇ alkoxy, C₂-C₇alkenoxy, cycloalkyloxy, aryloxy, heteroaryloxy, aryl-C₁-C₇ alkoxy orheteroaryl-C₁-C₇ alkoxy, an optionally substituted C₁-C₇ alkyl or C₂-C₇alkenyl, an optionally substituted aryl, heteroaryl or an optionallysubstituted aryl-C₁-C₇ alkyl group;R₁, R₂, and R₃ are independently selected from the group consisting of Hand C₁-C₇ alkyl;X is a C₃-C₁₈ cycloalkyl, heterocycloalkyl, aryl or heteroaryl each ofwhich may be optionally substituted;Q is a linker of between 1 and 3 atoms in length;Y is C₃-C₁₈ cycloalkyl, heterocycloalkyl, bridged cycloalkyl, bridgedheterocyloalkyl, aryl, heteroaryl, fused aryl-heterocycloalkyl, all ofwhich are independently optionally substituted once or more;

The optional substituent or substituents on R and R9 are independentlyselected from the group consisting of halogen, hydroxy, C₁-C₇ alkyl,mono or di-lower alkylamino, aminocarbonyl, mono or di-loweralkylaminocarbonyl, amino, carboxy, C₁-C₇ alkoxy, C₃-C₁₂ cycloalkyl,C₃-C₁₈ heterocycloalkyl, C₁-C₇ alkylcarbonyl, C₁-C₇ alkoxycarbonyl,nitryl, aryl; all of which, except halogen, are independently optionallysubstituted by one or more substituents, selected from the groupconsisting of halogen, hydroxyl, C₁-C₇ alkyl, mono or di-C₁-C₇alkylamino, aminocarbonyl, mono or di-C₁-C₇ alkylaminocarbonyl, amino,carboxy, C₁-C₇ alkoxy, C₃-C₁₂ cycloalkyl, C₃-C₁₈ heterocycloalkyl, C₁-C₇alkylcarbonyl, C₁-C₇ alkoxycarbonyl, nitryl, aryl.

The optional substituent or substituents on X are independently selectedfrom the group consisting of halogen, hydroxyl, C₁-C₇ alkyl, mono ordi-C₁-C₇ alkylamino, aminocarbonyl, mono or di-C₁-C₇ alkylaminocarbonyl,amino, carboxy, C₁-C₇ alkoxy, C₃-C₁₂ cycloalkyl, C₃-C₁₈heterocycloalkyl, C₁-C₇ alkylcarbonyl, C₁-C₇ alkoxycarbonyl, nitryl,aryl; all of which, except halogen, are independently optionallysubstituted by one or more substituents, selected from the groupconsisting of halogen, hydroxyl, C₁-C₇ alkyl, mono or di-C₁-C₇alkylamino, aminocarbonyl, mono or di-C₁-C₇ alkylaminocarbonyl, amino,carboxy, C₁-C₇ alkoxy, C₃-C₁₂ cycloalkyl, C₃-C₁₈ heterocycloalkyl, C₁-C₇alkylcarbonyl, C₁-C₇ alkoxycarbonyl, nitryl, aryl.

The optional substituent or substituents on Y are independently selectedfrom the group consisting of halogen, hydroxyl, C₁-C₇ alkyl, mono ordi-C₁-C₇ alkylamino, aminocarbonyl, mono or di-C₁-C₇ alkylaminocarbonyl,amino, carboxy, C₁-C₇ alkoxy, C₃-C₁₂ cycloalkyl, C₃-C₁₈heterocycloalkyl, C₁-C₇ alkylcarbonyl, C₁-C₇ alkoxycarbonyl, nitryl,aryl; all of which, except halogen, are independently optionallysubstituted by one or more substituents, selected from the groupconsisting of halogen, hydroxyl, C₁-C₇ alkyl, mono or di-C₁-C₇alkylamino, aminocarbonyl, mono or di-C₁-C₇ alkylaminocarbonyl, amino,carboxy, C₁-C₇ alkoxy, C₃-C₁₂ cycloalkyl, C₃-C₁₈ heterocycloalkyl, C₁-C₇alkylcarbonyl, C₁-C₇ alkoxycarbonyl, nitryl, aryl.

For the avoidance of doubt, the terms listed below are to be understoodto have the following meaning throughout the present description andclaims:

The term “lower”, when referring to organic radicals or compounds meansa compound or radical with may be branched or unbranched with up to andincluding 7 carbon atoms.

A lower alkyl group may be branched, unbranched or cyclic and contains 1to 7 carbon atoms, preferably 1 to 4 carbon atoms. Lower alkylrepresents, for example: methyl, ethyl, propyl, butyl, isopropyl,isobutyl, tertiary butyl or 2,2-dimethylpropyl.

A lower alkoxy group may be branched or unbranched and contains 1 to 7carbon atoms, preferably 1 to 6 carbon atoms. Lower alkoxy represents,for example: methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy ortertiary butoxy. Lower alkoxy includes cycloalkyloxy andcycloalkyl-lower alkyloxy.

A lower alkene, alkenyl or alkenoxy group is branched or unbranched andcontains 2 to 7 carbon atoms, preferably 1 to 4 carbon atoms andcontains at least one carbon-carbon double bond. Lower alkene, loweralkenyl or lower alkenyloxy represents for example vinyl, prop-1-enyl,allyl, butenyl, isopropenyl or isobutenyl and the oxy equivalentsthereof.

In the present application, oxygen containing substituents, e.g. alkoxy,alkenyloxy, alkynyloxy, carbonyl, etc. encompass their sulphurcontaining homologues, e.g. thioalkoxy, thioalkenyloxy, thioalkynyloxy,thiocarbonyl, sulphone, sulphoxide etc.

Halo or halogen represents chloro, fluoro, bromo or iodo.

Aryl represents carbocyclic aryl, heterocyclic aryl or biaryl.

Carbocyclic aryl is an aromatic cyclic hydrocarbon containing from 6 to18 ring atoms. It can be monocyclic, bicyclic or tricyclic, for examplenaphthyl, phenyl, or phenyl mono-, di- or trisubstituted by one, two orthree substituents.

Heterocyclic aryl is an aromatic monocyclic or bicyclic hydrocarboncontaining from 5 to 18 ring atoms one or more of which are heteroatomsselected from O, N or S. Preferably there are one or two heteroatoms.Heterocyclic aryl represents, for example: pyridyl, indolyl,quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl,benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl,isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl.Heterocyclic aryl also includes such substituted radicals.

Cycloalkyl represents a cyclic hydrocarbon containing from 3 to 12 ringatoms preferably from 3 to 6 ring atoms. Cycloalkyl represents, forexample: cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Thecycloalkyl may optionally be substituted.

Heterocycloalkyl represents a mono-, di- or tricyclic hydrocarbon whichmay be saturated or unsaturated and which contains one or more,preferably one to three heteroatoms selected from O, N or S. Preferablyit contains between three and 18 ring atoms. The term heterocycloalkylis intended also to include bridged heterocycloalkyl groups such as3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl.

Pharmaceutically acceptable prodrug esters are ester derivatives whichare convertible by solvolysis or under physiological conditions to thefree carboxylic acid of formula (I). Such esters are for example loweralkyl esters (such as methyl or ethyl esters), carboxy-lower alkylesters such as the carboxymethyl ester, nitrooxy-lower alkyl esters(such as the 4-nitrooxybutyl ester).

Referring to formula (I), preferably Z is NH, NCH₃, CH₂, S or O.

R is preferably hydroxy, an optionally substituted lower alkoxy,alkenoxy, cycloalkyl-lower alkyloxy, aryloxy, heteroaryloxy, aryl-loweralkyloxy or heteroaryl lower alkyloxy, an optionally substituted aryl,heteroaryl or an optionally substituted aryl-lower alkyl group.

More preferably, R is an oxy group, e.g. C₁-C₇ alkoxy. Yet morepreferably, R is a branched C₁-C₇ alkoxy or a substituted C₁-C₇ alkoxy.A preferred substituent for the substituted C₁-C₇ alkoxy is a furyl orbenzofuryl which is optionally substituted.

R9 is preferably hydrogen.

X is preferably selected from the group consisting of:

Most preferably, X is

Q is preferably defined by —CR₄R₅— or —CR₄R₅-Q₁- wherein Q₁ denotes—CR₆R₇— or —NR₈—; R₄, R₅, R₆ and R₇ and R₈ being independently selectedfrom the group consisting of H, an optionally substituted lower alkyl,an optionally substituted lower alkenyl, an optionally substituted arylor an optionally substituted aryl-lower alkyl group, for example methyl,(CH₃)₂CH—CH₂—, CH₃—C(═CH₂)—CH₂—, (CH₃)₃C—CH₂—, benzyl;

Q is more preferably selected from the group consisting of: —CH₂—,—CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH(CH₃)—CH₂—, —CH₂—CH(CH₃)—, —CH₂—NH₂—,—CH(CH₃)—NH—, —CH₂—N(CH₃)—, —CH₂—CH(CH₂OH)— or —CH(CH₃)—NH(CH₃)—;

Y is preferably selected from the group consisting of: piperidinyl,azepanyl, azocanyl, phenyl, tetrahydropyranyl,8-aza-bicyclo[3.2.1]oct-8-yl, tetrahydropyridinyl,octahydroquinolizinyl, hexahydro-pyrrolooxazinyl,octahydro-pyridooxazinyl each of which is optionally substituted.Preferred optional substituents for Y are: hydroxy, amino, halo, C₁-C₇alkyl.

A second aspect of the invention provides a compound of formula (II), ora pharmaceutically acceptable salt, ester or prodrug thereof:

wherein:

Z′ is NH, NCH₃, CH₂, S or O.

R′ is hydroxy, an optionally substituted C₁-C₇ alkoxy, cycloalkyl-C₁-C₇alkyloxy, aryloxy, heteroaryloxy or aryl-C₁-C₇ alkyloxy, an optionallysubstituted aryl, heteroaryl or an optionally substituted aryl-C₁-C₇alkyl group;X′ is selected from the group consisting of:

Q′ is selected from the group consisting of: —CH₂—, —CH₂—CH₂—,—CH₂—CH₂—CH₂—, —CH(CH₃)—CH₂—, —CH₂—CH(CH₃)—, —CH₂—NH₂—, —CH(CH₃)—NH—,—CH₂—N(CH₃)—, —CH₂—CH(CH₂OH)— or —CH(CH₃)—NH(CH₃)—;Y′ is C₃-C₁₈ cycloalkyl, heterocycloalkyl, bridged cycloalkyl, bridgedheterocyloalkyl, aryl, heteroaryl, fused aryl-heterocycloalkyl, all ofwhich are independently optionally substituted once or more;the optional substituent or substituents on R′ being independentlyselected from the group consisting of halogen, hydroxy, C₁-C₇ alkyl,mono or di-C₁-C₇ alkylamino, aminocarbonyl, mono or di-C₁-C₇alkylaminocarbonyl, amino, carboxy, C₁-C₇ alkoxy, C₃-C₁₂ cycloalkyl,C₃-C₁₈ heterocycloalkyl, C₁-C₇ alkylcarbonyl, C₁-C₇ alkoxycarbonyl,nitryl, aryl; all of which, except halogen, are independently optionallysubstituted by one or more substituents, selected from the groupconsisting of halogen, hydroxyl, C₁-C₇ alkyl, mono or di-C₁-C₇alkylamino, aminocarbonyl, mono or di-lower alkylaminocarbonyl, amino,carboxy, C₁-C₇ alkoxy, C₃-C₁₂ cycloalkyl, C₃-C₁₈ heterocycloalkyl, C₁-C₇alkylcarbonyl, C₁-C₇ alkoxycarbonyl, nitryl, aryl;the optional substituent or substituents on Y′ being independentlyselected from the group consisting of halogen, hydroxyl, C₁-C₇ alkyl,mono or di-C₁-C₇ alkylamino, aminocarbonyl, mono or di-C₁-C₇alkylaminocarbonyl, amino, carboxy, C₁-C₇ alkoxy, C₃-C₁₂ cycloalkyl,C₃-C₁₈ heterocycloalkyl, C₁-C₇ alkylcarbonyl, C₁-C₇ alkoxycarbonyl,nitryl, aryl; all of which, except halogen, are independently optionallysubstituted by one or more substituents, selected from the groupconsisting of halogen, hydroxyl, C₁-C₇ alkyl, mono or di-C₁-C₇alkylamino, aminocarbonyl, mono or di-C₁-C₇ alkylaminocarbonyl, amino,carboxy, C₁-C₇ alkoxy, C₃-C₁₂ cycloalkyl, C₃-C₁₈ heterocycloalkyl, C₁-C₇alkylcarbonyl, C₁-C₇ alkoxycarbonyl, nitryl, aryl.

Preferred compounds of formula I are:

-   4-Methoxy-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)piperidin-4-yl]amide-   4-Isopropoxy-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-Isopropoxy-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-Cyclopropylmethoxy-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-Cyclopropylmethoxy-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-Cyclopropylmethoxy-1H-indole-2-carboxylic acid    {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-Cyclopropylmethoxy-1H-indole-2-carboxylic acid    {1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-Isobutoxy-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-Isobutoxy-1H-indole-2-carboxylic acid    [1-(2-piperidin-1-yl-ethyl)-piperidin-4-yl]-amide-   4-Isobutoxy-1H-indole-2-carboxylic acid    {1-[2-(RS)-2-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-Isobutoxy-1H-indole-2-carboxylic acid    {1-[2-(4-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-Isobutoxy-1H-indole-2-carboxylic acid    {1-[2-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-Isobutoxy-1H-indole-2-carboxylic acid    {1-[2-((R)-3-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-Isobutoxy-1H-indole-2-carboxylic acid    {1-[2-((S)-3-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-Isobutoxy-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-Isobutoxy-1H-indole-2-carboxylic acid    {1-[2-((1R,3S,5S)-3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-ethyl]-piperidin-4-yl}-amide-   4-Isobutoxy-1H-indole-2-carboxylic acid    {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-Isobutoxy-1H-indole-2-carboxylic acid    [4-(2-azepan-1-yl-ethyl)-phenyl]amide-   4-Isobutoxy-1H-indole-2-carboxylic acid    (4-{[methyl-(tetrahydro-pyran-4-yl)-amino]-methyl}-cyclohexyl)-amide-   4-Isobutoxy-1H-indole-2-carboxylic acid    (4-{[methyl-(tetrahydro-pyran-4-yl)-amino]-methyl}-phenyl)-amide-   4-Isobutoxy-1H-indole-2-carboxylic acid    (4-{(R)-1-[methyl-(tetrahydro-pyran-4-yl)-amino]-ethyl}-phenyl)-amide-   4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid    {1-[2-(3-(R)-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid    {1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid    {1-[2-((1R,3S,5S)-3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-ethyl]-piperidin-4-yl}-amide-   4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid    {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid    {1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-(3-Methyl-butyloxy)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide    dihydrochloride-   4-Cyclopentylmethoxy-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(1,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-(2,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-(4-Methyl-pentyloxy)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(3,3-Dimethyl-butoxy)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(Furan-2-ylmethoxy)-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-Benzyloxy-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)piperidin-4-yl]amide-   4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(4-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(4-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(Benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(Benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(Benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(Benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-(Benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-(6-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(6-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(6-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(6-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(6-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-(5-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide-   4-(5-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(5-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-((3R,4R,5S)-4-hydroxy-3,5-dimethyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(5-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(5-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-(7-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(4,6-Difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(4,6-Difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(4,6-Difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(4,6-Difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(4,6-Difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(7-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(6-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(6-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(6-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(6-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(4-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(4-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(4-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-((3R,4R,5S)-4-hydroxy-3,5-dimethyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(4-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-(7-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(7-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    [1-(2-piperidin-1-yl-ethyl)-piperidin-4-yl]-amide-   4-(7-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(7-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(7-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(7-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-(6-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide-   4-(6-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-(6-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(6-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(6-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-(6-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-(5-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-(5-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(4-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide-   4-(4-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(4-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(4-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-(4-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-(4,6-dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(4,6-Dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(4,6-Dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(4,6-Dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-(4,6-Dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-(5,6-dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(5,6-Dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(5,6-Dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(5,6-Dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(5,6-Dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide    dihydrochloride-   4-(4-Ethoxy-phenyl)-1H-indole-2-carboxylic acid    {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-(4-Methoxy-phenyl)-1H-indole-2-carboxylic acid    {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-Phenoxy-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)piperidin-4-yl]-amide-   4-m-Tolyloxy-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)piperidin-4-yl]-amide-   4-m-Tolyloxy-1H-indole-2-carboxylic acid    {1-[2-(3-(RS)-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-m-Tolyloxy-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-p-Tolyloxy-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)piperidin-4-yl]-amide-   4-p-Tolyloxy-1H-indole-2-carboxylic acid    {1-[2-(3-(RS)-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-p-Tolyloxy-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(3-Fluoro-phenoxy)-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-(3-Fluoro-phenoxy)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(4-Fluoro-phenoxy)-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-(4-Fluoro-phenoxy)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(3,4-Difluoro-phenoxy)-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-(3,5-Difluoro-phenoxy)-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-(3,5-Difluoro-phenoxy)-1H-indole-2-carboxylic acid    {1-[2-(3-RS-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(3,5-Difluoro-phenoxy)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(6-Chloro-pyridin-2-yloxy)-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-Isobutoxy-1H-indole-2-carboxylic acid    [1-(octahydro-quinolizin-1-yl)methyl)-piperidin-4-yl]-amide    dihydrochloride-   4-Isobutoxy-1H-indole-2-carboxylic acid    [1-(1-methyl-piperidin-3-yl)methyl)-piperidin-4-yl]-amide-   4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid    {1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide-   4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid    {1-[(S)-2-((3R,4R)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid    {1-[(S)-2-((3S,4R,5S)-3,4-dihydroxy-5-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid    {1-[(R)-3-hydroxy-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide-   4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-((3R,4R)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-(2-Methyl-thiazol-4-ylmethoxy)-1H-indole-2-carboxylic acid    [1-(octahydro-quinolizin-1-yl)methyl)-piperidin-4-yl]-amide-   4-(Benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[2-(3,4-dihydroxy-5-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-(5-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-((3RS,4SR)-3,4-dihydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(S)-2-((3RS,4SR)-3,4-dihydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(9S,9aS)-1-(octahydro-pyrido[2,1-c][1,4]oxazin-9-yl)methyl]-piperidin-4-yl}-amide-   4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {1-[(8S,8aS)-1-(hexahydro-pyrrolo[2,1-c][1,4]oxazin-8-yl)methyl]-piperidin-4-yl}-amide-   4-(4-Methoxy-phenyl)-1H-indole-2-carboxylic acid    {1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide-   4-(4-Ethoxy-phenyl)-1H-indole-2-carboxylic acid    {1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide-   4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acid    {1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide-   4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acid    {1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-p-Tolyloxy-1H-indole-2-carboxylic acid    {1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide-   4-Isobutoxy-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-1S-methyl-ethyl)-piperidin-4-yl]-amide-   4-Isobutoxy-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-1R-methyl-ethyl)-piperidin-4-yl]-amide-   4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid    [1-(2S-azepan-1-yl-propyl)-piperidin-4-yl]-amide-   4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid    [1-(2R-azepan-1-yl-propyl)-piperidin-4-yl]-amide-   4-Isobutoxy-1H-indole-2-carboxylic acid    {1-[2-(3,6-dihydro-2H-pyridin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-Isobutoxy-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-azepan-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-Isobutoxy-1H-indole-2-carboxylic acid    {1-[2-(3-amino-azepan-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-Isobutoxy-1H-indole-2-carboxylic acid    {1-[2-(3-fluoro-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    [4-(2-piperidin-1-yl-ethyl)-phenyl]-amide-   4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid    {4-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-phenyl}-amide-   4-Phenyl-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)piperidin-4-yl]amide-   4-(4-Trifluoromethyl-phenyl)-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-p-Tolyl-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]amide-   4-(4-Dimethylamino-phenyl)-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-Benzo[1,2,5]oxadiazol-5-yl-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-(4-Methoxy-phenyl)-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-(3-Cyano-phenyl)-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)piperidin-4-yl]amide-   4-(4-Ethoxy-phenyl)-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)piperidin-4-yl]amide-   4-[3-(3-Methoxy-propoxy)-phenyl]-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-(4-Trifluoromethoxy-phenyl)-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-(2,4-Dimethoxy-phenyl)-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)piperidin-4-yl]-amide-   4-(3,4-Dimethoxy-phenyl)-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-Benzo[1,3]dioxol-5-yl-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-Pyridin-4-yl-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)piperidin-4-yl]amide-   4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide-   4-(4-Ethoxy-phenyl)-1H-indole-2-carboxylic acid    [1-(2-piperidin-1-yl-ethyl)-piperidin-4-yl]-amide-   4-(4-Methoxy-phenyl)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(4-Ethoxy-phenyl)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acid    {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide-   4-(4-Methoxy-phenyl)-1H-indole-2-carboxylic acid    {1-[2-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-ethyl]-piperidin-4-yl}-amide-   4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acid    {1-[2-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-ethyl]-piperidin-4-yl}-amide-   4-Hydroxy-1H-indole-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)piperidin-4-yl]amide-   4-Methoxy-benzo[b]thiophene-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]amide-   4-Isobutoxy-benzo[b]thiophene-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)piperidin-4-yl]-amide-   4-Isobutoxy-benzo[b]thiophene-2-carboxylic acid    [1-(2-piperidin-1-yl-ethyl)-piperidin-4-yl]-amide-   4-Methoxy-benzofuran-2-carboxylic acid    [1-(2-azepan-1-yl-ethyl)piperidin-4-yl]-amide

According to a third aspect of the invention there is provided acompound of formula (I) for use as a pharmaceutical for the prevention,amelioration or treatment of an autoimmune or inflammatory disease orcondition.

According to a fourth aspect of the invention there is provided aprocess for the preparation of a compound of formula (I) comprising:

(a) reacting a compound of formula (III):

wherein R″ is H or a lower alkyl group, with a compound of formulaNH₂—X-Q-Y, the groups R, R9, Z, X, Q and Y being defined above; or(b) for the preparation of compounds of formula (I) wherein X ispiperidin-4-yl and Q is —CH₂—CH₂—, and Y is a group having the formula—NR₇R₈ wherein N, R₇ and R₈ are linked to define collectively aheterocycloalkyl, bridged cycloalkyl, bridged heterocycloalkyl,heteroaryl, or fused aryl-heterocycloalkyl, reacting a compound offormula (IV):

with a compound of formula NHR₇R₈, wherein R₇ and R₈ are as definedabove, and R, R₉ and Z are as defined earlier; or(c) for the preparation of compounds of formula (I) wherein X ispiperidin-4-yl and Q is CH₂—, reacting a compound of formula (V):

in which R, R9 and Z are as defined above, with a compound of formulaHO—CH₂—Y, in which Y is as defined earlier; or(d) for the preparation of compounds of formula (I) wherein R is anoptionally substituted aryl group, appropriately substituting the Brgroup in a compound of formula (VI) for said substituted aryl group:

wherein Z, R9, X, Q and Y are as earlier defined;and recovering the resultant compounds of formula (I) in free or saltform.

The process of the invention is effected in conventional manner.

Process variant (a) is a condensation reaction between acid or ester andamine. It is conveniently effected by reacting the acid with the aminein the presence of coupling agents, for example TBTU/DIEA in a solventsuch as DMF, or by reacting the ester with the amine in the presence ofa coupling agent such as HOBT/EDC.

Process variant (b) is a condensation reaction which is convenientlycarried out using a reagent such as cyanomethyl-triphenyl phosphoniumiodide and Hunig's base.

Process variant (c) is a condensation reaction is also a condensationreaction which is conveniently carried out using a reagent such ascyanomethyl-triphenyl phosphonium iodide and Hunig's base.

Process variant (d) is a substitution reaction and is convenientlyeffected using the appropriate aryl-boronic acid and triphenylphosphinein the presence of lead (II) acetate.

The compounds of the invention can be recovered from the reactionmixture and purified in conventional manner. Isomers, such asenantiomers, may be obtained in conventional manner, e.g. by fractionalcrystallization or asymmetric synthesis from correspondingasymmetrically substituted, e.g. optically active, starting materials.

The starting materials and intermediates are either known or can beprepared according to known methods or analogously as described in theExamples.

According to a fifth aspect of the invention there is provided compoundobtainable by any one of the above mentioned processes.

According to a sixth aspect of the invention there is provided apharmaceutical composition comprising a compound of formula (I) inassociation with a pharmaceutically acceptable diluent or carrier.

According to a seventh aspect of the invention there is provided the useof a compound of formula (I) in the manufacture of a medicament for usein the treatment of an autoimmune or inflammatory disease or condition.

According to an eighth aspect of the invention there is provided amethod of inhibiting chemokine receptors or macrophage proteins or ofreducing inflammation in a subject in need of such treatment, whichmethod comprises administering to said subject an effective amount of acompound of formula (I).

According to a ninth aspect of the invention there is provided a methodof treating an inflammatory or autoimmune disease or condition,comprising administering to said subject an effective amount of acompound of formula (I).

Agents of the invention may be prepared by processes described below:

EXPERIMENTAL SECTION Abbreviations:

BOC: t-ButyloxycarbonylBoc2O: Di-t-butyl dicarbonate

DCC: Dicyclohexyl-carbodiimide DCE: Dichloroethane DCM: Dichloromethane

DEAD: Diethyl azadicarboxylate

DIEA: Ethyl-diisopropyl-amine

DMAP: Dimethyl-pyridin-4-yl-amine

DME: 1,2-Dimethoxy-ethane

DMF: N,N-Dimethyl formamideEDC: (3-Dimethylamino-propyl)-ethyl-carbodiimide hydrochloride

Ether: Ethoxy-ethane EtOH: Ethanol

EtOAc: Acetic acid ethyl esterHCl: Hydrochloric acid

HOBT: Benzotriazol-1-ol

LAH: Lithium aluminumhydrideLDA: Lithium diisopropylamine

MeOH: Methanol

NaOH: Sodium hydroxide

NMP: 1-Methyl-pyrrolidin-2-one

Pd/C: Palladium on carbonTBAF: Tetrabutylammonium fluorideTBME: t-Butyl-methyl etherTBDMS: t-Butyl-dimethyl-silylTBTU O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroboratet-BuOH 2-Methyl-propan-2-olTFA: Trifluoro-acetic acid

THF: Tetrahydrofuran

1H-NMR spectra are recorded on a Varian Gemini 400 MHz NMR spectrometer.Significant peaks are tabulated in the order: multiplicity (s, singlet;d, doublet; t, triplet; q, quartet; m, multiplet; br, broad) and numberof protons. Electron Spray Ionization (ESI) mass spectra are recorded ona Hewlett Packard 5989A mass spectrometer. Mass spectrometry results arereported as the ratio of mass over charge. Preparative HPLCpurifications are performed with XTerra™ RP18 19×150 mm columns, usingacetonitrile/water or MeOH/water as eluent systems. All reagents,starting materials and intermediates utilized in these examples areavailable from commercial sources or are readily prepared by methodsknown to those skilled in the art.

Synthesis of the Amine Building Blocks

The amines 1, 5, 7, 10, 12, 14, 17, 20, 21, 24, 27, 30, 35, 41, 50, 56,60, 61, 63, 67, 70 and 72 are prepared according the reaction schemesoutlined below.

Reaction Scheme 1:

Reaction Scheme 2:

Reaction Scheme 3:

Reaction Scheme 4:

Reaction Scheme 5:

Reaction Scheme 6:

Reaction Scheme 7:

Reaction Scheme 8:

Reaction Scheme 9:

Reaction Scheme 10:

Reaction Scheme 11:

Synthesis of 1-(2-Piperidin-1-yl-ethyl)-piperidin-4-ylaminetri-hydrochloride (1) (reaction scheme 1)

(1) (1-Benzyl-piperidin-4-yl)-carbamic acid tert-butyl ester (2)

1-Benzyl-piperidin-4-ylamine (50 g, 262.76 mmol) is dissolved in amixture of 200 ml of water, 145 ml of 2 molar aqueous sodium hydroxideand 350 ml of t-BuOH at 0° C. A solution of Boc2O (63.1 g, 1.1equivalents) in 150 ml of t-BuOH is added dropwise within one hour at 0°C. A white suspension is formed which is allowed to stir overnight atroom temperature. The reaction mixture is diluted with ether and washedwith water. The organic layers are dried over anhydrous sodium sulfateand evaporated under reduced pressure.

Yield: 71.5 g of a pale yellow solid (93%). MS (ESI): 291 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 7.2-7.35 (m, 5H), 6.77 (br d, 1H), 3.44 (s, 2H), 3.22(br m, 1H), 2.75 (m, 2H), 1.95 (dt, 2H), 1.68 (m, 2H), 1.38 (s, 9H),1.36 (dt 2H).

(2) Piperidin-4-yl-carbamic acid tert-butyl ester (3)

A solution of the ester 2 from above (66 g, 227.27 mmol) in 1 l ofethanol is hydrogenated under normal pressure with 10 g of Pd/C (10%)for 16 hours at room temperature. The mixture is filtered over celiteand evaporated under reduced pressure. Recrystallisation from ether gave34.5 g (76%) of white crystals.

MS (ESI): 201 [M+H]⁺, 401 [2M+H]+, 1H-NMR (DMSO-d₆): δ (ppm) 6.7 (br d,NH), 3.22 (br m, 1H), 2.88 (dt, 2H), 2.39 (dt, 2H), 1.8 (br s, NH), 1.6(dt, 2H), 1.35 (s, 9H), 1.18 (dt, 2H).

(3) 1-(2-Piperidin-1-yl-ethyl)-piperidin-4-A-carbamic acid tert-butylester (4)

Piperidin-4-yl-carbamic acid tert-butyl ester (3) (4.8 g, 23.72 mmol),1-(2-Chloro-ethyl)-piperidine hydrochloride (5.3 g, 26.09 mmol) and DIEA(8.9 ml, 52.18 mmol) are dissolved in 150 ml of chloroform and refluxedfor 18 hours. After addition of more 1-(2-Chloro-ethyl)-piperidinehydrochloride (2.65 g, 13.05 mmol) and DIEA (4.4 ml, 26.09 mmol) thereaction mixture is refluxed for another 4 hours. After cooling to roomtemperature, the mixture is diluted with DCM and washed with water and5% aqueous sodium hydrogen carbonate solution. Evaporation gave 7.3 g ofbrownish crystals which are recrystallized from ether/hexane.

Yield: 5.3 g (72%) of beige crystals. MS (ESI): 312 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 6.75 (br d, NH), 3.18 (br m, 1H), 2.8 (m, 2H),2.3-2.4 (m, 8H), 1.92 (dt, 2H), 1.65 (m, 2H), 1.48 (m, 4H), 1.38 (s,9H), 1.3-1.4 (m, 4H).

(4) 1-(2-Piperidin-1-yl-ethyl)-piperidin-4-ylamine tri-hydrochloride (1)

Ester 4 from above (5.2 g, 16.7 mmol) is suspended at 0° C. in 60 ml ofa 4M solution of HCl in dioxane and stirred at room temperature for 3hours. After evaporation under reduced pressure the crude product isdried at high vacuum.

Yield: 5.3 g (99%) of light beige crystals. MS (ESI): 212 [M+H]⁺, 1H-NMR(D₂O): δ (ppm) 4.14 (m, 2H), 4.04 (br m, 5H), 3.8 (m, 4H), 3.65 (dt,2H), 2.85 (d, 2H), 2.45 (m, 2H), 2.35 (m, 4H), 2.15 (m, 2H).

Synthesis of 1-(2-Azepan-1-yl-ethyl)-piperidin-4-ylaminetri-hydrochloride (S) (reaction scheme 1)

(1) [1-(2-Azepan-1-yl-ethyl)-piperidin-4-yl]-carbamic acid tert-butylester (6)

It is synthesized analogously to ester 4 starting from2-(hexamethylenimino)ethyl chloride (13.8 g) and ester 3 (12.4 g).

Yield: 14 g of a colorless solid (63%). MS (ESI): 326 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 6.75 (br d, NH), 3.18 (br m, 1H), 2.8 (m, 2H),2.3-2.6 (m, 8H), 1.95 (dt, 2H), 1.65 (m, 2H), 1.55 (m, 6H), 1.38 (s,9H), 1.3-1.4 (m, 4H).

(2) 1-(2-Azepan-1-yl-ethyl)-piperidin-4-ylamine tri-hydrochloride (5)

It is prepared analogously to 1 starting from ester 6 (14 g).

Yield: 13 g (90%) of a colorless solid. MS (ESI): 226 [M+H]⁺, 1H-NMR(120° C., DMSO-d₆): δ (ppm) 8.5 (br, NH3+), 3.5 (m, 5H), 3.4 (m, 2H),3.3 (m, 4H), 2.97 (m, 2H), 2.18 (m, 2H), 2.05 (m, 2H), 1.9 (m, 4H), 1.7(m, 4H).

Synthesis of 1-[2-(4-Methyl-piperidin-1-O-ethyl]-piperidin-4-ylaminetri-hydrochloride (7) (reaction scheme 2)

(1) [1-(2-Hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester(8)

To a solution of piperidin-4-yl-carbamic acid tert-butyl ester 3 (10 g,50 mmol) in 100 ml of methanol are added sodium carbonate (21.2 g, 200mmol) and 2-bromoethanol (7.1 ml, 100 mmol). The mixture is stirred overnight. The solvents are then evaporated and the residue is trituratedwith DCM, filtered and evaporated again. The crude product is purifiedby chromatography using EtOAc/MeOH (saturated with ammonia): 9/1.

Yield: 8.07 g (66%). MS (ESI): 245.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)6.75 (br d, 1H), 4.34 (t, 1H), 3.46 (q, 2H), 3.19 (br m, 1H), 2.8 (m,2H), 2.35 (t, 2H), 1.95 (m, 2H), 1.66 (m, 2H), 1.39 (s, 9H), 1.35 (m,2H).

(2) {1-[2-(4-Methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-carbamic acidtert-butyl ester (9)

A mixture of ester 8 (3 g, 12.28 mmol), 4-methyl piperidine (1.46 ml,12.28 mmol) and DIEA (2.7 ml, 15.96 mmol) in 30 ml of propionitrile istreated with solid cyanomethyl-trimethyl-phosphonium iodide (3.58 g,14.74 mmol) and heated at reflux for 3 hours. After cooling to roomtemperature, a 2M-K2CO3 solution is added until basic and the mixture isextracted twice with DCM. The organic layers are washed with brine,dried over anhydrous sodium sulfate and evaporated. The crude materialis purified by chromatography using EtOAc/MeOH (saturated with ammonia):9/1.

Yield: 2 g (50%). MS (ESI): 326.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 6.74(br d, 1H), 3.16 (m, 1H), 2.78 (m, 4H), 2.33 (br s, 4H), 1.86 (m, 4H),1.64 (m, 2H), 1.53 (m, 2H), 1.36 (s, 9H), 1.32 (m, 3H), 1.08 (m, 2H),0.86 (d, 3H).

(3) 1-[2-(4-Methyl-piperidin-1-yl)-ethyl]-piperidin-4-ylaminetri-hydrochloride (7)

The tert-butyl ester 9 (2 g, 6.14 mmol) is suspended in 10 ml ofdioxane. DCM is then added until the solid dissolved. To this mixture,4M−HCl in dioxane (12.3 ml, 49.2 mmol) is added. After stirring overnight the solvents are evaporated to leave a white solid product.

Yield: 2.06 g (100%). MS (ESI): 226.2 [M+H]⁺

Synthesis of1-[24(RS)-2-Methyl-piperidin-1-yl)-ethyl]-piperidin-4-ylaminetrihydrochloride (10) (reaction scheme 2)

(1) {1-[2-((S)-2-Methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester (11)

It is prepared analogously to 9 starting from tert-butyl ester 8 (2 g,8.19 mmol), (S)-2-methyl-piperidine (0.985 ml, 8.19 mmol), DIEA (1.8 ml,10.65 mmol) and cyanomethyl-trimethyl-phosphonium iodide (2.39 g, 9.83mmol).

Yield: 1.35 g (51%). MS (ESI): 326.3 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm)4.42 (br d, 1H), 3.47 (m, 1H), 2.84 (m, 4H), 2.47 (m, 3H), 2.15-2.35 (m,2H), 2.1 (m, 2H), 1.92 (m, 2H), 1.2-1.75 (m, 8H), 1.44 (s, 9H), 1.08 (d,3H).

(2) 1-[2-((RS)-2-Methyl-piperidin-1-yl)-ethyl]-piperidin-4-ylaminetri-hydrochloride (10)

It is prepared by BOC-cleavage of tert-butyl ester 11 (1.3 g, 3.99 mmol)with 4M−HCl in dioxane (8 ml, 32 mmol) as described for amine 7.

Yield: 1.3 g (97%). MS (ESI): 226.2 [M+H]⁺

Synthesis of (R)-1-[2-(4-Amino-piperidin-1-yl)-ethyl]-piperidin-3-oltri-hydrochloride (12) (reaction scheme 2)

(1) {1-[2-((R)-3-Hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester (13)

It is prepared analogously to 9 starting from tert-butyl ester 8 (3.52g, 14.41 mmol), (R)-3-hydroxy-piperidine hydrochloride (2.18 g, 15.85mmol), DIEA (5.6 ml, 33.14 mmol) and cyanomethyl-trimethyl-phosphoniumiodide (4.2 g, 17.29 mmol).

Yield: 1.71 g (36%). MS (ESI): 328.2 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm)4.61 (br d, 1H), 3.89 (m, 3H), 3.53 (m, 1H), 3.03 (m, 2H), 2.55-2.73 (m,6H), 2.44 (m, 1H), 2.3 (m, 2H), 1.83-2.02 (m, 3H), 1.5-1.7 (m, 4H), 1.44(s, 9H).

(2) (R)-1-[2-(4-Amino-piperidin-1-yl)-ethyl]-piperidin-3-oltri-hydrochloride (12)

It is prepared by BOC-cleavage of tert-butyl ester 13 (1.7 g, 5.19 mmol)with 4M−HCl in dioxane (10.4 ml, 41.52 mmol) as described for amine 7.

Yield: 1.69 g (96%). MS (ESI): 228.3 [M+H]⁺

Synthesis of(3S,4S)-1-[2-(4-Amino-piperidin-1-yl)-ethyl]-3-methyl-piperidin-4-oltrihydrochloride (14)

(1) 2,2-Dimethyl-propionic acid(3S,4S)-1-[2-(4-tert-butoxycarbonylamino-piperidin-1-yl)-ethyl]-3-methyl-piperidin-4-ylester (15)

A solution of tert-butyl ester 8 (4.8 g, 19.65 mmol) and triethylamine(4.1 ml, 29.47 mmol) in 150 ml of DCM is cooled to −78 C. Triflicanhydride (4.3 ml, 25.54 mmol) is slowly added and stirring continuedfor 1 hour. The mixture is then allowed to warm up to 0 C and a solutionof 2,2-dimethyl-propionic acid 3S-methyl-piperidin-4S-yl ester, 17,preparation see below, (3.72 g, 18.66 mmol) in 20 ml of DCM is added at0° C. Stirring is continued at room temperature for 1 hour. The mixtureis washed twice with water, dried over sodium sulphate, filtered andevaporated.

Yield: 9.3 g (>100%, contained some triethylamine). MS (ESI): 426.3[M+H]⁺.

(2){1-[24(3S,4S)-4-Hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester (16)

Crude 15 (8.2 g, 19.27 mmol) is treated with NaOMe (0.5M in methanol, 77ml, 38.5 mmol) and heated under reflux for 24 hours. The solvent is thenevaporated, the residue taken up in DCM and extracted with 1N—NaOH andbrine. Drying and evaporation gave a brown oil which is purified bychromatography on silicagel using DCM (saturated with ammonia) and MeOH(from 1% to 5%).

Yield: 3.07 g (46%). MS (ESI): 342.3 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm)4.51 (br d, 1H), 3.5 (br m, 1H), 3.17 (td, 1H), 2.85-3.08 (m, 4H), 2.63(m, 4H), 2.1-2.35 (m, 3H), 1.48-2.04 (m, 9H), 1.42 (s, 9H), 0.99 (d,3H).

(3) (3S,4S)-1-[2-(4-Amino-piperidin-1-yl)-ethyl]-3-methyl-piperidin-4-oltrihydrochloride (14)

It is prepared by BOC-cleavage of tert-butyl ester 16 (3.07 g, 8.98mmol) with 4M−HCl in dioxane (11.2 ml, 44.8 mmol) as described for amine7.

Yield: 3.1 g (98%). MS (ESI): 328.2 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm) 4.61(br d, 1H), 3.89 (m, 3H), 3.53 (m, 1H), 3.03 (m, 2H), 2.55-2.73 (m, 6H),2.44 (m, 1H), 2.3 (m, 2H), 1.83-2.02 (m, 3H), 1.5-1.7 (m, 4H), 1.44 (s,9H).

Synthesis of 2,2-Dimethyl-propionic acid (3S,4S)-3-methyl-piperidin-4-ylester (17) (reaction scheme 2)

(1) Step A: trans-2,2-Dimethyl-propionic acid1-benzyl-3-methyl-piperidin-4-yl ester (18)

To a cis/trans mixture of 1-benzyl-3-methyl-piperidin-4-ol (50 g, 243mmol, prepared as described in Can. J. Chem. (1972) 50, 803) in THF isadded triethylamine (51 ml, 365 mmol) followed by 2,2-dimethyl-propionylchloride (45 ml, 365 mmol). The reaction is exothermic and a precipitateis formed. The mixture is heated under reflux for 18 hours, cooled,filtered and washed with ether. The organic layers are washed with1N—NaOH and brine, dried and evaporated. The crude is purified bychromatography on silicagel using hexane and EtOAc (5%) to give puretrans-isomer as a colourless oil.

Yield: 38 g (54%). MS (ESI): 290.1 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 7.3(m, 5H), 4.29 (td, 1H), 3.45 (d, 2H), 2.74 (d, 2H), 2.05 (td, 1H), 1.8(m, 3H), 1.46 (m, 1H), 1.14 (s, 9H), 0.8 (d, 3H).

(2) Step B: trans-2,2-dimethyl-propionic acid 3-methyl-piperidin-4-ylester (19)

The trans-ester 18 (104 g, 359 mmol) is hydrogenated in methanol (1700ml) with Pd/C in the presence of one equivalent of HCl (431 ml, 359mmol, 1.25M in MeOH). The mixture is filtered and evaporated. Theresidue is redissolved in ether and extracted with 1N—NaOH and brine.Evaporation gives a colourless oil.

Yield: 62.7 g (87%). MS (ESI): 200.2 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm)4.46 (td, 1H), 3.06 (m, 2H), 2.68 (td, 1H), 2.35 (m, 1H), 1.94 (m, 1H),1.68 (m, 2H), 1.34-1.46 (m, 1H), 1.2 (s, 9H), 0.96 (d, 3H).

(3) Step C: 2,2-Dimethyl-propionic acid (3S,4S)-3-methyl-piperidin-4-ylester (17)

Racemic 19 (62.7 g, 314.4 mmol) is dissolved in EtOAc (300 ml) and asolution of L-(−)-0,0′-Dibenzoyl tartaric acid (56.3 g, 157.2 mmol) inEtOAc (450 ml) is added. The formed solid is filtered off, washed withcold EtOAc and dried. It is then re-crystallized from hot methanol (400ml). The crystals are collected and the free base is liberated bytreatment with 1N—NaOH and extraction with ether.

Yield: 13 g (21%). MS and 1H-NMR are identical to racemic 19.[α]_(D)=65.1 (c=1 in MeOH).

Synthesis 2,2-Dimethyl-propionic acid (3R,4R)-3-methyl-piperidin-4-ylester (20)

The mother liquor of 17 from above is treated with 1N—NaOH to obtain thefree base which is then crystallized with D-(+)-O,O′-Dibenzoyl tartaricacid as described above to give the antipode 20.

Yield: 16 g (25%). MS and 1H-NMR are identical to racemic 19.[α]_(D)=−64.7 (c=1 in MeOH)

Synthesis of 1-[2-(4-Amino-piperidin-1-yl)-ethyl]-piperidin-4-oltri-hydrochloride (21) (reaction scheme 3)

(1) 1-(2-Hydroxy-ethyl)-piperidin-4-ol (22)

Piperidin-4-ol (5 g, 49.4 mmol) is dissolved in 200 ml of ethanol andanhydrous sodium carbonate (21 g, 197.6 mmol) is added. 2-Bromo-ethanol(6.9 ml, 98.8 mmol) is added dropwise and the reaction mixture isrefluxed for 16 hours. After evaporation under reduced pressure themixture is stirred with 200 ml of DCM and filtered. The clear filtrateis evaporated under reduced pressure and dried at high vacuum.

Yield: 4.3 g (60%) of a colorless oil.

MS (ESI): 146 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 4.52 (d, 1H), 4.32 (t,1H), 3.48 (dt, 2H), 3.4 (m, 1H), 2.7 (m, 2H), 2.35 (t, 2H), 2.05 (m,2H), 1.68 (m, 2H), 1.3-1.4 (m, 2H).

(2) {1-[2-(4-Hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester (23)

Piperidin-4-yl-carbamic acid tert-butyl ester 3 (5 g, 25 mmol),1-(2-Hydroxy-ethyl)-piperidin-4-ol 22 (4 g, 27.5 mmol) and DIEA (5.6 ml,32.5 mmol) are suspended in 25 ml of propionitril.Cyanomethyl-trimethyl-phosphonium iodide (4 g, 30 mmol) is added and thereaction mixture is refluxed. Additional portions ofcyanomethyl-trimethyl-phosphonium iodide (1.5 g, 11.25 mmol) are addedafter 90 minutes and after 3 hours. After cooling to room temperature, asolution of potassium carbonate (4 g) in 250 ml of water is added andthe product is isolated by extraction with DCM. Evaporation underreduced pressure gave 6.9 g of a red oil which could be crystallizedfrom ether.

Yield: 2.2 g (27%) of colorless crystals.

MS (ESI): 328 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 6.72 (br d, 1H), 4.5 (d,1H), 3.42 (m, 1H), 3.2 (m, 1H), 2.8 (m, 2H), 2.7 (m, 2H), 2.35 (m, 4H),2.0 (dt, 2H), 1.9 (dt, 2H), 1.68 (m, 4H), 1.4 (s, 9H), 1.35 (m, 4H).

(3) 1-[2-(4-Amino-piperidin-1-yl)-ethyl]-piperidin-4-oltri-hydrochloride (21)

Ester 23 (2.2 g, 6.72 mmol) is dissolved in 4M HCl in dioxane at 0° C.and stirred at room temperature for 3 hours. After evaporation of thesolvent the product is dried at high vacuum.

Yield: 2.3 g (100%) of a white solid. MS (ESI): 228 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 5 (m, 1H), 3.4 (m, 4H), 2.7 (m, 4H), 2.4 (m, 2H),1.85-2.0 (m, 4H), 1.65 (m, 4H), 1.35 (m, 4H), 1.2 (m, 2H).

Synthesis of8-[(2-(4-Amino-piperidin-1-yl)-ethyl]-8-aza-bicyclo[3.2.1]octan-3-oltri-hydrochloride (24) (reaction scheme 3)

(1) 8-(2-Hydroxy-ethyl)-8-aza-bicyclo[3.2.1]octan-3-ol (25)

8-Aza-bicyclo[3.2.1]octan-3-ol hydrochloride (5.1 g, 31.45 mmol)) andsodium carbonate (13.3 g, 125.8 mmol) are suspended in 150 ml of ethanolat room temperature. 2-Bromo-ethanol (4.4 ml, 62.9 mmol) is addeddropwise within 20 minutes and the reaction mixture is refluxed for 15hours. After cooling to room temperature the reaction mixture isevaporated under reduced pressure. The mixture is stirred with 200 ml ofDCM and filtered. The clear filtrate is dried over anhydrous sodiumsulfate, filtered, evaporated under reduced pressure and dried at highvacuum.

Yield: 5.4 g (100%) of a colorless oil.

MS (ESI): 172 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 4.25 (d, 2H), 3.78 (t,1H), 3.42 (t, 2H), 3.06 (m, 2H), 2.36 (t, 2H), 2.03 (m, 2H), 1.85 (m,2H), 1.75 (m, 2H), 1.55 (d, 2H).

(2){1-[2-(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester (26)

Piperidin-4-yl-carbamic acid tert-butyl ester 3 (1 g, 5 mmol),8-(2-hydroxy-ethyl)-8-aza-bicyclo[3.2.1]octan-3-ol 25 (1 g, 5.5 mmol)and DIEA (1.1 ml, 6.5 mmol) are dissolved in 5 ml of propionitril.Cyanomethyl-trimethyl-phosphonium iodide (792 mg, 6 mmol) is added understirring and the reaction mixture is refluxed and followed by TLC.Additional cyanomethyl-trimethyl-phosphonium iodide (400 mg) is addedafter 2 hours and the mixture is refluxed for another hour. Aftercooling to room temperature, DCM. The combined organic layers are washedwith brine, dried over anhydrous a solution of potassium carbonate (4 g)in 250 ml of water is added and the product is isolated by extractionwith sodium sulfate, filtered and evaporated under reduced pressure. Thecrude product (1.9 g) is crystallized from ether.

Yield: 940 mg (53%) of light beige crystals. MS (ESI): 354 [M+H]⁺,1H-NMR (DMSO-d₆): δ (ppm) 6.73 (br d, 1H), 4.25 (d, OH), 3.8 (m, 1H),3.17 (m, 1H), 3.08 (m, 2H), 2.8 (m, 2H), 2.35 (m, 4H), 2.0 (m, 2H), 1.92(m, 2H), 1.85 (dt, 2H), 1.78 (m, 2H), 1.65 (m, 2H), 1.53 (m, 2H), 1.38(s, 9H), 1.33 (m, 2H).

(3) 8-[2-(4-Amino-piperidin-1-yl)-ethyl]-8-aza-bicyclo[3.2.1]octan-3-oltrihydrochloride (24)

Ester 26 (4.5 g, 12.73 mmol) is dissolved in 4M HCl in dioxane at 0° C.and stirred at room temperature for 3 hours. After evaporation of thesolvent the product is dried at high vacuum.

Yield: 4.6 g (100%) of a white solid. MS (ESI): 254 [M+H]⁺.

Synthesis of1-[2-((2S,6R)-2,6-Dimethyl-piperidin-1-yl)-ethyl]-piperidin-4-ylaminetrihydrochloride (27) (reaction scheme 3)

(1) {1-[2-(2,6-Dimethyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester (28)

Compound 28 is prepared analogously to 25 starting fromcis-2,6-dimethylpiperidin (6.4 ml, 44.17 mmol) and bromethanol (6.1 ml,88.33 mmol).

Yield: 3.9 g (56%) of a yellow oil. MS (ESI): 158.1 [M+H]⁺]+, 1H-NMR(DMSO-d₆): δ (ppm) 4.48 (br, 1H), 3.4 (t, 2H), 2.6 (t, 2H), 2.4 (m, 2H),1.1-1.6 (m, 6H), 1.03 (d, 6H).

(2) {1-[2-(2,6-Dimethyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester (29)

Compound 29 is prepared analogously to 26 starting from compound 28(3.85 g, 24.48 mmol) and piperidin-4-yl-carbamic acid tert-butyl ester 3(4.46 g, 22.25 mmol).

Yield: 6.16 g (82%) of a yellow oil. MS (ESI): 340.4 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 6.73 (br d, 1H), 3.18 (m, 1H), 2.75 (m, 2H), 2.65 (m,2H), 2.35 (m, 2H), 2.25 (m, 2H), 1.92 (m, 2H), 1.65 (m, 2H), 1.57 (m,2H), 1.49 (m, 2H), 1.38 (s, 9H), 1.35 (m, 2H), 1.12 (m, 2H), 1.03 (d,6H).

(3)1-[2-((2S,6R)-2,6-Dimethyl-piperidin-1-yl)-ethyl]-piperidin-4-ylaminetrihydrochloride (27)

Compound 27 is prepared analogously to 24 starting from the BOCprotected derivative 29 (6.16 g, 18.14 mmol).

Yield: 6.3 g (100%) of a white solid. MS (ESI): 240.3 [M+H]⁺.

Synthesis of(R)-14(3a,7a)-2,2-Dimethyl-tetrahydro-[1,3]-dioxolo[4,5-c]pyridin-5-yl)-propan-2-ol(30) (reaction scheme 4)

(1) 3,6-Dihydro-2H-pyridine-1-carboxylic acid benzyl ester (31)

1,2,3,6-Tetrahydro-pyridine (3 g, 36.1 mmol) are treated with 10%aqueous sodium carbonate (2.1 ml) and cooled to 0° C. Within 1 h, benzylchloroformiate (Z-chloride, 5.1 ml, 36 mmol) is added dropwise within 1h. After additional stirring for 2 h, the mixture is treated with 30 mlof brine and extracted four times with diethyl ether. The organic layersare dried over sodium sulphate and evaporated. The crude product, 7 g ofa colorless oil, is purified by Flash-chromatography (silica gel,cyclohexane/ethyl acetate 9:1).

Yield: 3.63 g (46%) of a colorless oil. MS (ESI): 218 [M+H]⁺, 1H-NMR(CDCl₃): δ (ppm) 7.28-7.4 (m, 5H), 5.83 (m, 1H), 5.66 (m, 1H), 5.15 (s,2H), 3.95 (m, 2H), 3.58 (t, 2H), 2.15 (m, 2H).

(2) 3,4-Dihydroxy-piperidine-1-carboxylic acid benzyl ester (32)

31 (3.63 g, 16.7 mmol) is dissolved in 16 ml of a 1:1 mixture of waterand acetone. After addition of N-methyl-morpholine-N-oxide (2.9 g, 24.8mmol), a 1% solution of osmium tetroxide in tert. Butanol (7.23 ml, 0.28mmol) is added. The mixture is stirred at room temperature for 20 h.Then 70 ml of a saturated sodium bisulfite solution is added. After 15min stirring at room temperature, the reaction mixture is extracted withethyl acetate. The organic layers are dried over sodium sulphate andevaporated. The crude product, 4.7 g of a yellow oil, is purified byFlash-chromatography (silica gel, ethyl acetate).

Yield: 3.83 g (91%). MS (ESI): 252 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm)7.27-7.4 (m, 5H), 5.13 (s, 2H), 3.88 (m, 1H), 3.79 (m, 2H), 3.66 (m,2H), 3.5 (dd, 1H), 3.34 (m, 1H), 2.13 (m, 2H), 1.82 (m, 1H), 1.7 (m,1H).

(3) 2,2-Dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyridine-5-carboxylicacid benzyl ester (33)

32 from above (3.72 g, 14.8 mmol) is dissolved in 20 ml ofdichloromethane. After addition of 2,2-dimethoxypropane (3.6 ml, 30mmol) and p-toluene sulfonic acid (141 mg, 0.7 mmol) the mixture isstirred at room temperature for 4 h. Then the mixture is diluted with 30ml of dichloromethane, washed subsequently with 1N NaOH and brine, driedover sodium sulphate and evaporated. The crude racemic product, 4.32 gof a yellow oil, is separated into its enantiomers by chiral HPLC(chiralcel, OJ, 20 um, hexane/isopropanol 9:1).

Yield: 810 mg peak 1 and 942 mg (peak2) (40%) MS (ESI): 292.2 [M+H]⁺,1H-NMR (CDCl₃): δ (ppm) 7.25-7.4 (m, 5H), 5.14 (s, 2H), 4.18-4.4 (m,2H), 3.7-3.82 (m, 1H), 3.38-3.58 (m, 3H), 1.74-2.0 (m, 2H), 1.44 (s,3H), 1.35 (s, 3H).

(4) 2,2-Dimethyl-hexahydro-[1,3]dioxolo[4,5-c]pyridine (34) (singlecis-enantiomer, absolute configuration unknown)

33 (peak 1 from above) (450 mg, 1.54 mmol) is dissolved in 10 ml ofmethanol. After addition of 10% palladium on carbon (45 mg) the mixtureis hydrogenated at room temperature for 20 h. Then the mixture isfiltrated over celite. Evaporation gave 240 mg (99%) of a colorless oil.

MS (ESI): 158.2 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm) 4.25 (m, 1H), 4.12 (m,1H), 2.9-3.1 (m, 3H), 2.78 (m, 1H), 1.85-2.40 (m, 3H), 1.52 (s, 3H),1.38 (s, 3H).

(5)1-(2,2-Dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl)-propan-2-ol(30) (single enantiomer, absolute configuration of dioxol unknown)

34 (90 mg, 0.57 mmol), (R)-(+)-propylenoxide (166 mg, 2.8 mmol), andtriethylamine (160 ul, 1.1 mmol) are dissolved in 2 ml of ethanol andstirred at room temperature for 4 h. The reaction mixture is dilutedwith 20 ml of ethyl acetate, washed subsequently with 1N NaOH and brine,dried over sodium sulphate and evaporated. The crude product, 100 mg ofa yellow oil, is purified by Flash-chromatography (silica gel,dichloromethane/methanol/ammonia 95:5:0.5).

Yield: 70 mg (57%). MS (ESI): 216.2 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm)4.03-4.28 (m, 2H), 3.9 (m, 1H), 2.2-3.08 (m, 6H), 1.36-2.13 (m, 3H),1.51 (s, 3H), 1.38 (s, 3H), 1.12-1.22 (dd, 3H).

Synthesis of(R)-1-(2,2,7-trimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl)-propan-2-ol(35) (reaction scheme 5)

(1) Trifluoro-methanesulfonic acid1-benzyl-3-(R,S)-methyl-1,2,3,6-tetrahydropyridin-4-yl ester (36)

1M lithium-bis-(trimethylsilyl)-amid solution in THF (540 ul, 0.54 mmol)is diluted with 1 ml of THF and cooled to −78° C. A solution of1-benzyl-3-methyl-4-piperidone (100 mg, 0.49 mmol) in 0.5 ml THF isadded via syringe within 5 min. After stirring for 2 h at thistemperature, a solution of N-phenyl-trifluoromethansulfonimid (188 mg,0.52 mmol) in 1 ml of THF is added within 10 min. The beige suspensionis stirred for another 4 h at 0° C. The yellow solution is quenched with1 ml of saturated ammonium chloride solution, diluted with ice-coldwater and three times extracted with ethyl acetate. The organic layersare washed with brine, dried over sodium sulphate and evaporated. Thecrude product, 311 mg of a yellow oil, is purified byFlash-chromatography (silica gel, cyclohexane/ethyl acetate 4:1).

Yield: 127 mg (77%) of a colorless oil. MS (ESI): 336 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 7.22-7.36 (m, 5H), 5.89 (dd, 1H), 3.54-3.65 (m, 2H),3.05 (br s, 2H), 2.75 (m, 1H), 2.59 (m, 1H), 2.32 (m, 1H), 1.06 (d, 3H).

(2) 1-Benzyl-3-(R,S)-methyl-1,2,3,6-tetrahydro-pyridine (37)

36 from above (100 mg, 0.3 mmol), palladium-(II)-acetate (1.34 mg, 6umol), triphenylphosphin (3.1 mg, 12 umol) and triethylamine (125 ul,0.9 mmol) are dissolved in 1 ml of DMF. After addition of formic acid(22.5 ul, 0.6 mmol) the mixture is stirred for 1 h at 60° C. Thereaction mixture is diluted with ethyl acetate, washed subsequently with1N NaOH and brine, dried over sodium sulphate and evaporated. The crudeproduct, 78 mg of a yellow oil, is purified by Flash-chromatography(silica gel, cyclohexane/ethyl acetate 3:1).

Yield: 42 mg (75%) of a yellow oil. MS (ESI): 188.2 [M+H]⁺, 1H-NMR(CDCl₃): δ (ppm) 7.23-7.41 (m, 5H), 5.62 (s, 2H), 3.63 (br s, 2H), 3.12(d, 1H), 2.83 (m, 2H), 2.48 (m, 1H), 2.02 (br s, 1H), 0.96 (d, 3H).

(3) (3RS,4SR,5RS)-1-Benzyl-5-methyl-piperidine-3,4-diol (racemic) (38)

37 (570 mg, 3 mmol) is dissolved in 10 ml of a 1:1 mixture of water andacetone. After addition of N-methyl-morpholine-N-oxide (529 mg, 4.5mmol), a 2.5% solution of osmium tetroxide in tert. Butanol (527 ul, 52umol) is added. The mixture is stirred at room temperature for 24 h.Then 10 ml of a saturated sodium bisulfite solution is added. After 15min stirring at room temperature, the reaction mixture is extracted withethyl acetate. The organic layers are washed subsequently with 1N NaOHand brine, dried over sodium sulphate and evaporated. The crude product,460 mg of a dark brown oil, is purified by Flash-chromatography (silicagel, dichloromethane/methanol/ammonia 95:5:0.5).

Yield: 290 mg (43%) of the cis diol, trans to the methyl group and 20 mg(3%) of the all-cis derivative. MS (ESI): 222 [M+H]⁺, 1H-NMR (DMSO-d₆):δ (ppm) 7.17-7.32 (m, 5H), 4.21 (d, 1H), 4.04 (br d, 1H), 3.58 (m, 1H),3.41 (dd, 2H), 3.02 (m, 1H), 2.62 (m, 1H), 2.56 (br d, 1H), 2.12 (br d,1H), 1.69-1.88 (m, 2H), 0.86 (d, 3H).

(4)(3aRS,7RS,7aSR)-5-Benzyl-2,2,7-trimethyl-hexahydro-[1,3]dioxolo[4,5-c]pyridine(racemic) (39)

38 from above (290 mg, 1.3 mmol) is dissolved in 4 ml ofdichloromethane. After portionwise addition of 2,2-dimethoxypropane (1.6ml, 13 mmol) and p-toluene sulfonic acid (300 mg, 1.6 mmol) the mixtureis stirred at room temperature for 16 h. Then the mixture is dilutedwith dichloromethane, washed subsequently with 1N NaOH and brine, driedover sodium sulphate and evaporated. The crude product, 333 mg of ayellow oil, is purified by Flash-chromatography (silica gel,cyclohexane/ethyl acetate 3:1).

Yield: 303 mg (89%) MS (ESI): 262.2 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm)7.20-7.40 (m, 5H), 4.19 (br s, 1H), 3.69 (br s, 1H), 3.43-3.63 (m, 2H),2.89 (m, 1H), 2.53 (m, 2H), 2.02 (m, 1H), 1.88 (m, 1H), 1.53 (s, 3H),1.37 (s, 3H), 1.00 (d, 3H).

(5)(3aRS,7RS,7aSR)-5-Benzyl-2,2,7-trimethyl-hexahydro-[1,3]dioxolo[4,5-c]pyridine(racemic) (40)

39 from above (250 mg, 0.96 mmol) is dissolved in 5 ml of isopropanol.After addition of 10% palladium on carbon (25 mg) the mixture ishydrogenated at room temperature for 16 h. Then the mixture is filtratedover celite. Evaporation gave 170 mg (100%) of a colorless oil.

MS (ESI): 172.2 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm) 4.05 (m, 1H), 3.67 (dd,1H), 3.39 (d, 1H), 2.98 (m, 2H), 2.21 (t, 1H), 2.05 (m, 1H), 1.73 (m,1H), 1.52 (s, 3H), 1.37 (s, 3H), 0.98 (d, 3H).

(6)1-(2,2,7-Trimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyridin-5-yl)-propan-2-ol(35) (mixture of diastereomers)

40 (175 mg, 1 mmol), (R)-(+)-propylenoxide (297 mg, 5.1 mmol), andtriethylamine (285 ul, 2 mmol) are dissolved in 3 ml of ethanol andstirred at room temperature for 5 h. After evaporation the residue isdissolved in ethyl acetate, washed subsequently with 1N NaOH and brine,dried over sodium sulphate and evaporated. The crude product, 214 mg ofa yellow oil, is purified by Flash-chromatography (silica gel,dichloromethane/methanol/ammonia 95:5:0.5).

Yield: 140 mg (60%). MS (ESI): 172.2 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm)4.05 (m, 1H), 3.67 (dd, 1H), 3.39 (d, 1H), 2.98 (m, 2H), 2.21 (t, 1H),2.05 (m, 1H), 1.73 (m, 1H), 1.52 (s, 3H), 1.37 (s, 3H), 0.98 (d, 3H).

Synthesis of(3R,4R,5S)-1-[2-(4-Amino-piperidin-1-yl)-ethyl]-3,5-dimethyl-piperidin-4-oltri-hydrochloride (41) (reaction scheme 6)

(1) N′-[1-Benzyl-3-methyl-piperidin-(4E)-ylidene]-N,N-dimethyl-hydrazine(42)

N,N-dimethylhydrazine (3 ml, 39.3 mmol) and1-benzyl-3-methyl-piperidin-4-one (4 g, 19.7 mmol) are dissolved in 50ml of ethanol and refluxed for 18 hours. The reaction mixture isevaporated under reduced pressure and dried at high vacuum.

Yield: 4.8 g of a pale oil (99%). MS (ESI): 246 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 7.29 (m, 4H), 7.23 (m, 1H), 3.48 (m, 2H), 2.8 (m,1H), 2.65 (m, 1H), 2.35-2.55 (m, 2H), 2.29 (s, 6H), 2.25 (m, 1H),1.9-2.1 (m, 1H), 1.00 (d, 3H).

(2)N′-(1-Benzyl-3,5-dimethyl-piperidin-4-ylidene)-N,N-dimethyl-hydrazine(43)

Diisopropylamine (3.3 ml, 23.5 mmol) is dissolved in 20 ml of THF andcooled to −5° C. A 1.6M solution of n-butyllithium in THF (14.7 ml, 23.5mmol) is added dropwise within 10 min. After additional 10 min at −5°C., a solution of 42 (4.8 g, 19.6 mmol) in 30 ml of THF is added within20 min (the color of the reaction mixture changed to red). Now, thesolution is cooled to −78 C. Methyliodide (1.33 ml, 21.5 mmol) is addeddropwise within 15 min and the mixture is allowed to warm to roomtemperature over night. Dichloromethane is added and the solution iswashed with water. Evaporation gave 5 g of a colorless oil, which isfurther purified by flash-chromatography (silicagel, ethylacetate/hexanes 1:1)

Yield: 1.7 g of a white solid (33%). MS (ESI): 260 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 7.33 (m, 4H), 7.22 (m, 1H), 3.48 (m, 2H), 3.37 (m,1H), 2.68 (m, 1H), 2.59 (m, 1H), 2.43 (m, 1H), 2.43 (m, 1H), 2.29 (s,6H), 2.15 (m, 1H), 2.0 (m, 1H), 1.23 (d, 6H).

(3) 1-Benzyl-3,5-dimethyl-piperidin-4-one (44)

43 (1.7 g, 6.5 mmol) is dissolved in a 1.25M solution of HCl in methanol(20 ml, 25 mmol) and refluxed for 1.5 h The reaction mixture isevaporated under reduced pressure and dried at high vacuum. The residue(1.7 g of a colorless oil) is dissolved in ethyl acetate and treatedwith 5M NaOH. The organic layers are evaporated under reduced pressure.

Yield: 1.4 g of a colorless oil (84%). MS (ESI): 218 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 7.3 (m, 4H), 7.25 (m, 1H), 3.58 (m, 2H), 3.07 (m,2H), 2.68 (m, 2H), 1.97 (dd, 2H), 0.82 (d, 6H).

(4) 1-Benzyl-3,5-dimethyl-piperidin-4-ol (45)

Sodiumboronhydride (121 mg, 3.2 mmol) is added to a solution of 44 (1.4g, 6.4 mmol) in 15 ml of methanol and the mixture is stirred at roomtemperature for 30 min. The mixture is evaporated, and the residue isdissolved in ethyl acetate and washed with water.

Yield: 1.4 g of a colorless oil (99%). MS (ESI): 220 [M+H]⁺.

(5) Acetic acid (3S,4R,5R)-1-benzyl-3,5-dimethyl-piperidin-4-yl ester(46)

DMAP (40 mg, 0.3 mmol) is added to a solution of 45 (1.4 g, 6.4 mmol) in10 ml of pyridine. After addition of acetic anhydride (0.9 ml, 9.5 mmol)the mixture is stirred at 110° C. for 2 h. The mixture is evaporated,and the residue is dissolved in dichloromethane and washed with water.Evaporation gave 1.6 g of a colorless oil, which is further purified byflash-chromatography (silicagel, ethyl acetate/hexanes 1:9)

Yield: 0.7 g of a colorless oil (42%, fraction 1). MS (ESI): 262 [M+H]⁺,1H-NMR (DMSO-d₆): δ (ppm) 7.2-7.3 (m, 5H), 4.18 (dd, 1H), 3.42 (s, 2H),2.8 (m, 2H), 2.05 (s, 3H), 1.7-1.8 (m, 4H), 0.72 (d, 6H).

(6) Acetic acid (3R,4R,5S)-3,5-dimethyl-piperidin-4-yl ester (47)

Palladium hydroxide on carbon (20%, 300 mg) is placed into a flaskfilled with argon and carefully covered with 25 ml of methanol. Asolution of 46 (0.7 g, 2.7 mmol) in methanol is added and the mixture ishydrogenated at room temperature for 15 h. After filtration over celite,the filtrate is evaporated and dried under high vacuum.

Yield: 0.41 g of a colorless oil (89%). MS (ESI): 172 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 4.22 (dd, 1H), 2.8 (dd, 2H), 2.15 (dd, 2H), 2.05 (s,3H), 1.5 (m, 2H), 0.7 (d, 6H).

(7) Acetic acid(3S,4R,5R)-1-[2-(4-tert-butoxycarbonylamino-piperidin-1-yl)-ethyl]-3,5-dimethyl-piperidin-4-yester (48)

47 (2.3 g, 13.4 mmol) is dissolved in 5 ml of propionitril and afteraddition of 8 (3.3 g, 13.4 mmol), cyanomethyl-trimethyl-phosphoniumiodide (4.4 g, 33.6 mmol) and N-ethyldiisopropylamine (11.5 ml, 67.1mmol) the mixture is refluxed for 24 h (TLC control). Then the mixtureis evaporated under reduced pressure. The residue is diluted with ethylacetate, washed 10% K2CO3- and NaCl-solution, and dried over Na2SO4.

Yield: 3.3 g of a brown oil (62%). MS (ESI): 398 [M+H]⁺.

(8){1-[24(3S,4R,5R)-4-Hydroxy-3,5-dimethyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester (49)

48 (3.3 g, 8.3 mmol) is dissolved in 100 ml of methanol and afteraddition of NaOMe powder (2.2 g, 41.5 mmol) the mixture is refluxed for6 h (TLC control). Then the mixture is evaporated under reducedpressure. The residue is diluted with ethyl acetate, washed with water,and dried over Na2SO4. Evaporation gave 3.1 g of a brown oil. The crudeproduct is purified by recrystallization from ether.

Yield: 800 mg of a colorless solid (27%). MS (ESI): 356 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 6.7 (br d, 1H), 4.4 (d, 1H), 3.15 (br m, 1H), 2.75(m, 4H), 2.4 (m, 1H), 2.3 (m, 4H), 1.9 (m, 2H), 1.3-1.7 (m, 8H), 1.38(s, 9H), 0.85 (d, 6H).

(9)3R,4R,5S)-1-[2-(4-Amino-piperidin-1-yl)-ethyl]-3,5-dimethyl-piperidin-4-oltrihydrochloride (41)

49 is dissolved in a 4M solution of HCl in dioxane (20 ml) and stirredfor 4 h (TLC control) at room temperature. Then the mixture is cooleddown to 0 C and filtrated. The residue is washed with ether. Evaporationgave 510 mg (89%) of grey crystals.

MS (ESI): 256 [M+H]⁺.

Synthesis of1-[(S)-2-(4-Amino-piperidin-1-yl)-1-methyl-ethyl]-piperidin-4-oltri-hydrochloride (50) (reaction scheme 7)

(1) 2,2-Dimethyl-propionic acid 1-benzyl-piperidin-4-yl ester (51)

A solution of 1-benzyl-piperidin-4-ol (25 g, 130.7 mmol) andtriethylamine (36.1 ml, 261.4 mmol) in 250 ml of THF is treated with2,2-dimethyl-propionyl chloride (32.2 ml, 261.4 mmol). The suspension isheated under reflux over night. The solvent is evaporated, the residuetaken up in DCM and washed with saturated sodium bicarbonate solutionand brine. Drying and evaporation gave an orange oil.

Yield: 38.3 g (100% crude). MS (ESI): 276 [M+H]⁺, 1H-NMR (CDCl₃): δ(ppm) 7.31 (m, 4H), 7.25 (m, 1H), 4.79 (m, 1H), 3.5 (s, 2H), 2.61 (m,2H), 2.32 (m, 2H), 1.86 (m, 2H), 1.69 (m, 2H), 1.18 (s, 9H).

(2) 2,2-Dimethyl-propionic acid piperidin-4-yl ester (52)

A solution of piperidine 51 (35.99 g, 130.7 mmol) in methanol ishydrogenated with Pd/C in the presence of one equivalent of HCl (104.5ml, 130.7 mmol, 1.25M in MeOH). After filtration and evaporation, thecrude is taken up in ether and washed with 1N—NaOH and brine. Drying,evaporation and distillation (0.08 mbar, 75-90 C) gave a colourless oil.Yield: 17.98 g (74%).

MS (ESI): 186 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 9.22 (br s, 1H), 4.89(m, 1H), 3.08 (m, 4H), 1.99 (m, 2H), 1.78 (m, 2H), 1.15 (s, 9H).

(3) 2,2-Dimethyl-propionic acid 14(R)-2-hydroxy-propyl)-piperidin-4-ylester (53)

A solution of piperidine 52 (2 g, 10.8 mmol) and (R)-2-Methyl-oxirane(3.78 ml, 54 mmol) in 2 ml of ethanol is stirred for 24 hours in aclosed flask. The solvent is evaporated and the residue distilled in aKugelrohr apparatus (0.08 mbar, 75-90 C).

Yield: 2.58 g (98%).

MS (ESI): 244.2 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm) 4.65 (m, 1H), 4.1 (br s,1H), 3.72 (m, 1H), 2.55 (m, 2H), 2.31 (m, 2H), 2.23 (m, 1H), 2.14 (m,1H), 1.75 (m, 2H), 1.55 (m, 2H), 1.14 (s, 9H), 1.03 (d, 3H),[α]_(D)=−23.1 (c=1 in MeOH)

(4) 2,2-Dimethyl-propionic acid1-[(S)-2-(4-tert-butoxycarbonylamino-piperidin-1-yl)-1-methyl-ethyl]-piperidin-4-ylester (54)

A solution of alcohol 53 (1.26 g, 5.16 mmol) and triethylamine (1.43 ml,10.32 mmol) in 80 ml of DCM is cooled to −78 C. Triflic anhydride (0.85ml, 5.16 mmol) is slowly added and stirring continued for 1 hour. Themixture is then allowed to warm up to 0 C and cooled back to −78 C after15 minutes. A solution of piperidin-4-yl-carbamic acid tert-butyl ester,3, (1.03 g, 5.16 mmol) in 40 ml of DCM is slowly added at −78 C. Aftercomplete addition, the cooling bath is removed and the dark solution isallowed to warm up to room temperature. The mixture is washed twice withwater, dried over sodium sulphate, filtered and evaporated. The crude ispurified by chromatography on silicagel using DCM (saturated withammonia) and MeOH (1%).

Yield: 1.7 g (77%).

MS (ESI): 426.3 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm) 4.74 (m, 1H), 4.43 (m,1H), 3.43 (br m, 1H), 2.89 (m, 1H), 1.97-2.82 (m, 11H), 1.87 (m, 4H),1.64 (m, 2H), 1.43 (s, 9H), 1.38 (m, 1H), 1.19 (s, 9H), 1.0 (d, 3H).[α]_(D)=−9.3 (c=1 in MeOH)

(5){1-[(S)-2-(4-Hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-carbamicacid tert-butyl ester (55)

Ester 54 from above (1.7 g, 3.52 mmol) is treated with NaOMe (0.5M inmethanol, 21 ml, 10.5 mmol) and heated under reflux for 24 hours. Thesolvent is then evaporated, the residue taken up in DCM and extractedwith 1N—NaOH and brine. After drying and evaporation the crued ispurified by chromatography on silicagel using DCM (saturated withammonia) and MeOH (from 1% to 3%) to give a white powder.

Yield: 0.77 g (56%). MS (ESI): 342.3 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm)4.43 (m, 1H), 3.64 (m, 1H), 3.43 (m, 1H), 2.88 (m, 1H), 2.75 (m, 4H),1.8-2.45 (m, 10H), 1.3-1.65 (m, 5H), 1.44 (s, 9H), 0.99 (d, 3H).[α]_(D)=−15.3 (c=1 in MeOH).

(6) 1-[(S)-2-(4-Amino-piperidin-1-yl)-1-methyl-ethyl]-piperidin-4-oltrihydrochloride (50)

It is prepared by BOC-cleavage of tert-butyl ester 55 (0.666 g, 1.95mmol) with 4M−HCl in dioxane (2.93 ml, 11.72 mmol) as described foramine 7.

Yield: 0.64 g (93%). MS (ESI): 242.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)10.5-10.85 (br m, 2H), 8.3-8.8 (br m, 3H), 2.75-4.15 (br m, 15H),1.6-2.3 (br m, 7H), 1.39 (d, 3H). [α]_(D)=+13.2 (c=1 in MeOH)

Synthesis of(3S,4S)-1-[(S)-2-(4-Amino-piperidin-1-yl)-1-methyl-ethyl]-3-methyl-piperidin-4-oltri-hydrochloride (56) (reaction scheme 7)

(1) 2,2-Dimethyl-propionic acid(3S,4S)-1-((R)-2-hydroxy-propyl)-3-methyl-piperidin-4-yl ester (57)

A solution of piperidine 17 (2 g, 10.8 mmol) and (R)-2-Methyl-oxirane(3.78 ml, 54 mmol) in 2 ml of ethanol is stirred for 24 hours in aclosed flask. The solvent is evaporated and the residue distilled in aKugelrohr apparatus (0.08 mbar, 75-90 C).

Yield: 2.58 g (98%). MS (ESI): 258.2 [M+H]⁺, 1H-NMR (CD₃OD): δ (ppm)4.39 (td, 1H), 3.82 (m, 1H), 2.95 (m, 1H), 2.76 (m, 1H), 2.42 (td, 1H),2.17-2.33 (m, 2H), 1.96 (m, 1H), 1.75-1.9 (m, 2H), 1.62 (m, 1H), 1.2 (s,9H), 1.13 (d, 3H), 0.89 (d, 3H). [α]_(D)=−23.1 (c=1 in MeOH)

(2) 2,2-Dimethyl-propionic acid(3S,4S)-1-[(S)-2-(4-tert-butoxycarbonylamino-piperidin-1-yl)-1-methyl-ethyl]-3-methyl-piperidin-4-ylester (58)

A solution of alcohol 57 (1.26 g, 5.16 mmol) and triethylamine (1.43 ml,10.32 mmol) in 80 ml of DCM is cooled to −78 C. Triflic anhydride (0.85ml, 5.16 mmol) is slowly added and stirring continued for 1 hour. Themixture is then allowed to warm up to 0 C and cooled back to −78 C after15 minutes. A solution of piperidin-4-yl-carbamic acid tert-butyl ester,3, (1.03 g, 5.16 mmol) in 40 ml of DCM is slowly added at −78 C. Aftercomplete addition, the cooling bath is removed and the dark solution isallowed to warm up to room temperature. The mixture is washed twice withwater, dried over sodium sulphate, filtered and evaporated. The crude ispurified by chromatography on silicagel using DCM (saturated withammonia) and MeOH (1%).

Yield: 1.7 g (77%). MS (ESI): 440.3 [M+H]⁺, 1H-NMR (CD₃OD): δ (ppm) 4.3(td, 1H), 3.34 (m, 1H), 3.01 (m, 1H), 2.78-2.91 (m, 4H), 2.52 (dd, 1H),2.42 (td, 1H), 2.02-2.3 (m, 4H), 1.94 (m, 1H), 1.84 (m, 3H), 1.5 (m,3H), 1.45 (s, 9H), 1.21 (s, 9H), 1.04 (d, 3H), 0.9 (d, 3H). [α]_(D)=−9.3(c=1 in MeOH)

(3){1-[(S)-2-(3S,4S)-4-Hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-carbamicacid tert-butyl ester (59)

Ester 58 from above (1.7 g, 3.52 mmol) is treated with NaOMe (0.5M inmethanol, 21 ml, 10.5 mmol) and heated under reflux for 24 hours. Thesolvent is then evaporated, the residue taken up in DCM and extractedwith 1N—NaOH and brine. After drying and evaporation the crued ispurified by chromatography on silicagel using DCM (saturated withammonia) and MeOH (from 1% to 3%) to give a white powder.

Yield: 0.77 g (56%). MS (ESI): 356.3 [M+H]⁺, 1H-NMR (CD₃OD): δ (ppm)4.86 (s, 1H), 3.32 (m, 1H), 2.94-3.06 (m, 2H), 2.72-2.87 (m, 3H), 2.49(dd, 1H), 2.34 (td, 1H), 2.14-2.28 (m, 2H), 1.97-2.1 (m, 2H), 1.75-1.93(m, 3H), 1.53 (m, 4H), 1.44 (s, 9H), 1.04 (d, 3H), 0.97 (d, 3H).[α]_(D)=−15.3 (c=1 in MeOH)

(4)(3S,4S)-1-[(S)-2-(4-Amino-piperidin-1-yl)-1-methyl-ethyl]-3-methyl-piperidin-4-oltri-hydrochloride (56)

It is prepared by BOC-cleavage of tert-butyl ester 59 (0.666 g, 1.95mmol) with 4M−HCl in dioxane (2.93 ml, 11.72 mmol) as described foramine 7.

Yield: 0.64 g (93%). MS (ESI): 256.2 [M+H]⁺, 1H-NMR (CD₃OD): δ (ppm)4.25 (br m, 1H), 4.03 (br m, 3H), 3.05-3.9 (m, 9H), 1.95-2.55 (m, 7H),1.54 (d, 3H), 1.1 (d, 3H). [α]_(D)=+13.2 (c=1 in MeOH)

Synthesis 2,2-Dimethyl-propionic acid(3S,4S)-1-((S)-2-hydroxy-3-trityloxy-propyl)-3-methyl-piperidin-4-ylester (60)

(S)-2-Trityloxymethyl-oxirane (636 mg, 2 mmol) and2,2-dimethyl-propionic acid (3S,4S)-3-methyl-piperidin-4-ylester (17,400 mg, 2 mmol) are dissolved in 7 ml of ethanol and stirred at roomtemperature for 23 h. The white suspension is heated to 40° C. andstirred for additional 2 h. The reaction mixture is evaporated underreduced pressure and the crude product is purified byFlash-chromatography. (silica gel, 20% ethyl acetate in cyclohexane).

Yield: 681 mg (66%) of a white foam. MS (ESI): 516.4 [M+H]⁺, 1H-NMR(CDCl₃): δ (ppm) 7.4 (d, 6H), 7.31 (dd, 6H), 7.23 (dd, 3H), 4.62 (d,1H), 4.22 (m, 1H), 3.74 (m, 1H), 2.95 (d, 2H), 2.72 (m, 2H), 2.22-2.41(m, 2H), 2.07 (m, 1H), 1.58-1.84 (m, 3H), 1.14 (s, 9H), 0.76 (d, 3H).

Synthesis of(1-[(1S,9aR)-1-(Octahydro-quinolizin-1-yl)methyl]-piperidin-4-ylaminetrihydrochloride (61) (reaction scheme 8)

(1){1-[(1S,9aR)-1-(Octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-carbamicacid tert-butyl ester (62)

3 (3 g, 15 mmol) is dissolved in 150 ml of propionitril.Ethyldiisopropylamine (10.2 ml, 60 mmol), (−)-lupinine (2.5 g, 15 mmol)and cyanomethyl-trimethyl-phosphonium iodide (Zaragoza reagent, 7.3 g,30 mmol) are added. The reaction mixture is heated to 120° C. andstirred for 22 hours. Then the mixture is evaporated under reducedpressure. The residue is dissolved with ethyl acetate, washed 10% K2CO3-and NaCl-solution, and dried over Na2SO4. Evaporation gave 5.7 g of abrown oil. The crude product is purified by Flash-chromatography (ethylacetate, then methanol/ethyl acetate (4:6), silicagel).

Yield: 4.3 g (81.7%) of a brown oil. MS (ESI): 352 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 6.7 (br d, 1H), 3.2 (m, 1H), 2.7-2.75 (m, 4H), 2.4(dd, 1H), 2.2 (dd, 1H), 1.38 (s, 9H), 1.15-2.0 (m, 20H).

(2) 1-[(1S,9aR)-1-(Octahydro-quinolizin-1-yl)methyl]-piperidin-4-ylaminetrihydrochloride (61)

The ester 62 (3.8 g, 10.8 mmol) is dissolved in 15 ml of dioxane andafter addition of 70 ml of a 4M solution of HCl in do of HCl in dioxanthe mixture is stirred for 4 hours at RT. The product is filtered offand is used in the next step without further purification.

Yield: 3.9 g (100%). MS (ESI): 252 [M+H]⁺.

Synthesis of(9R,9aS)-1-(Octahydro-pyrido[2,1-c][1,4]oxazin-9-yl)-methanol (racemate)(63) (reaction scheme 9)

(1) 4-(3-Bromo-propyl)-morpholine-3,5-dione (64)

A pale yellow suspension of morpholine-3,5-dione (1.2 g, 10 mmol), of1,3-dibromopropane (3.4 ml, 33 mmol), and potassium carbonate (2.7 g, 19mmol) in 23 ml of 2-butanone is refluxed under an argon atmosphere for22 hours. After cooling, the suspension is concentrated on a rotaryevaporator, poured into ice/water, and extracted twice with ethylacetate. The combined organic phases are washed with brine, dried overanhydrous sodium sulphate, and evaporated. The residual yellow oil (2.06g) is purified by chromatography (Biotage 40 Mi, I=15 cm,cyclohexane/ethyl acetate 3:1).

Yield: 1.24 g (52.5%) of a colorless oil. MS (EI): 235 [M]⁺, 1H-NMR(CDCl₃): δ (ppm) 4.37 (s, 4H), 3.95 (t, 2H), 3.39 (t, 2H), 2.18 (m, 2H).

(2) 4-Oxo-1,3,4,6,7,8-hexahydro-pyrido[2,1-c][1,4]oxazine-9-carboxylicacid ethyl ester (65)

To an ice-cold suspension of sodium hydride (150 mg, 60% in mineral oil3.75 mmol) in 26 ml of anhydrous THF under argon is added a solution oftriethyl phosphonoacetate (0.31 ml, 1.5 mmol) in 6 ml of anhydrous THF.The suspension is stirred at RT for 2 hrs, then 64 (354 mg, 1.5) in 6 mlof THF is added, and the resulting mixture is refluxed for 10 hours.After cooling, the suspension is concentrated on a rotary evaporator,poured onto ice/sat. aqueous ammonium chloride solution, and extractedtwice with ethyl acetate. The combined organic phases are washed withbrine, dried over anhydrous sodium sulphate, and evaporated. Theresidual yellow oil (339 mg) is purified by chromatography (Biotage 12Mi, I=15.5 cm, cyclohexane/ethyl acetate 3:1).

Yield: 60.3 mg (17.8%) of a colorless oil. MS (ESI): 226 [M+H]⁺, 1H-NMR(CDCl₃): δ (ppm) 4.94 (s, 2H), 4.27 (s, 2H), 4.20 (q, 2H), 3.75 (dd,2H), 2.45 (m, 2H), 1.88 (m, 2H), 1.30 (t, 3H)

(3) (9RS,9aSR)-4-Oxo-octahydro-pyrido[2,1-c][1,4]oxazine-9-carboxylicacid ethyl ester (racemate) (66)

A solution of 65 (225 mg, 1.0 mmol) in 5 ml of acetic acid ishydrogenated over 225 mg of platinum dioxide at RT and normal pressurefor 18 hours. Another 225 mg of platinum dioxide is added andhydrogenation continued for 24 hours. The black suspension is dilutedwith 10 ml of DCM and filtered through a pad of celite. The filtrate isevaporated to give 268 mg of a yellow oil which is purified bychromatography (Biotage 12Si, 1=7.5 cm, ethyl acetate/ethanol 9:1).

Yield: 144 mg (63.3%) of a yellow oil. MS (ESI): 228 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 4.45 (m, 1H), 4.00 (m, 2H), 3.9-3.75 (m, 4H), 3.60(m, 1H), 2.65 (m, 1H), 2.55 (m, 1H), 1.90 (m, 2H), 1.75 (m, 1H), 1.45(m, 1H), 1.16 (t, 3H).

(4) (9RS,9aSR)-1-(Octahydro-pyrido[2,1-c][1,4]oxazin-9-yl)-methanol(racemate) (63)

To a solution of 66 (114 mg, 0.5 mmol) in 5 ml of anhydrous THF is addedLAH (40 mg, 1.0 mmol) and the mixture refluxed for 9 hours. The mixtureis cooled to 0° C. and treated successively with 0.04 ml of water, 3Naqueous sodium hydroxide (0.04 ml, 0.12), and 0.12 ml of water. Themixture is stirred for 15 min. and then extracted three times with DCM.The combined organic phases are dried over anhydrous sodium sulphate andevaporated under educed pressure. The residual pale yellow oil (75 mg)is purified by chromatography (Biotage 12 Si, I=7.5 cm, DCM/MeOH/conc.Ammonia 95:4.5:0.5).

Yield: 35.1 mg (41.0%) of a pale yellow oil. MS (ESI): 172 [M+H]⁺,1H-NMR (DMSO-d₆): δ (ppm) 4.30 (br s, 1H), 3.65-3.55 (m, 4H), 3.50-3.35(m, 2H), 2.70 (br d, 1H), 2.55 (br d, 1H), 2.10-1.95 (m, 2H), 1.85-1.60(m, 2H), 1.60-1.50 (m, 2H), 1.35-1.20 (m, 2H).

Synthesis of(8R,8aS)-1-(hexahydro-pyrrolo[2,1-c][1,4]oxazin-8-yl)-methanol(racemate) (67) (reaction scheme 10)

(1) 4-Oxo-3,4,6,7-tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylicacid ethyl ester (68)

To a suspension of sodium hydride (480 mg, 60% in mineral oil, 12 mmol)in 10 ml of anhydrous THF is added morpholine-3,5-dione (1.2 g, 10 mmol)in 20 ml of THF under an argon atmosphere. After 10 min.,1-carbethoxycyclopropyltriphenylphosphonium tetrafluoroborate (Fuchs'reagent, 6.8 g, 11 mmol)) in 20 ml of THF are added and the mixture isrefluxed for 21 hours. After cooling, the suspension is concentrated ona rotary evaporator, poured onto ice/sat. sodium bicarbonate solution,and extracted three times with ether. The combined organic phases arewashed with brine, dried over anhydrous sodium sulphate, and evaporated.The residual yellow oil (3.04 g) is purified by chromatography (Silicagel 60, 0.063-0.2 mesh, cyclohexane/ethyl acetate 1:1).

Yield: 1.08 g (51.2%) of a colorless solid. MS (EI): 211 [M]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 4.77 (s, 2H), 4.17 (s, 2H), 4.11 (q, 2H), 3.82 (m,2H), 2.70 (m, 2H), 1.22 (t, 3H).

(2) (8RS,8aSR)-4-Oxo-hexahydro-pyrrolo[2,1-c][1,4]oxazine-8-carboxylicacid ethyl ester (racemate) (69)

A solution of 68 (1.056 g, 5.0 mmol) in 25 ml of acetic acid ishydrogenated over 1.056 g of platinum dioxide at RT and normal pressurefor 18 hours. The black suspension is diluted with 20 ml of DCM andfiltered through a pad of celite. The filtrate is evaporated to give1.09 g of a yellow oil which is purified by chromatography (Silica gel60, 0.063-0.2 mesh, ethyl acetate/ethanol 9:1).

Yield: 809 mg (75.7%) of a yellow oil. MS (ESI): 214 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 4.15-3.80 (m, 6H), 3.70-3.05 (m, 4H), 2.70-1.90 (m,2H), 1.18 (t, 3H).

(3) (8RS,8aSR)-1-(Hexahydro-pyrrolo[2,1-c][1,4]oxazin-8-yl)-methanol(racemate) (67)

To a solution of 69 (1.1 g, 5.0 mmol) in 50 ml of anhydrous THF areadded LAH (400 mg, 10 mmol) and the mixture refluxed for 18 hours. Themixture is cooled to 0° C. and treated successively with 0.4 ml ofwater, 0.4 ml of 3N aq. sodium hydroxide, and 1.2 ml of water. Themixture is stirred for 15 min. and then extracted three times with DCM.The combined organic phases are dried over anhydrous sodium sulphate andevaporated. The residual yellow oil (880 mg) is purified bychromatography (Silica gel 60, 0.063-0.2 mesh, DCM/MeOH/conc. ammonia90:9:1).

Yield: 552 mg (70.2%) of a pink oil. MS (ESI): 158 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 4.42 (br s, 1H), 3.85 (m, 1H), 3.65 (m, 1H), 3.35 (m,2H), 3.15 (m, 1H), 2.95 (m, 1H), 2.85 (m, 1H), 2.15-1.90 (m, 5H), 1.75(m, 1H), 1.20 (m, 1H).

Synthesis of 4-(2-Azepan-1-yl-ethyl)-phenylamine di-hydrochloride (70)

(1) 1-[2-(4-Nitro-phenyl)-ethyl]-azepane (71)

1-(2-Bromo-ethyl)-4-nitro-benzene (10 g, 43.47 mmol) is added underargon to a mixture of azepane (4.9 ml, 43.47 mmol) and potassiumcarbonate (6 g, 43.47 mmol) in 100 ml of DMF. After stirring over nightat room temperature, the mixture is filtered and evaporated under highvacuum. The residue is dissolved in ethyl acetate, washed with water andbrine and dried over sodium sulfate. Evaporation gave 9.1 g (84%) of ayellow oil.

MS (ESI): 247.2 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm) 8.15 (d, 2H), 7.55 (d,2H), 2.87 (t, 2H), 2.73 (t, 2H), 2.65 (t, 4H), 1.5-1.6 (m, 8H).

(2) 4-(2-Azepan-1-yl-ethyl)-phenylamine di-hydrochloride (70)

Compound 71 (9.1 g, 36.65 mmol) is hydrogenated for 3 h at roomtemperature with palladium on carbon in 150 ml of ethanol and 18.3 ml of4M aqueous hydrochloric acid. The mixture is filtered over celite andevaporated.

Yield: 10.7 g (100%) of a beige solid. MS (ESI): 219 [M+H]⁺, 1H-NMR(CDCl₃): δ (ppm) 10.85 (br, 1H), 9.8 (br, 3H), 7.3 (m, 2H), 7.2 (m, 2H),3.42 (m, 2H), 3.25 (m, 2H), 3.18 (m, 2H), 3.08 (m, 2H), 1.85 (m, 4H),1.68 (m, 2H), 1.58 (m, 2H).

Synthesis of[(R)-1-(4-Amino-phenyl)-ethyl]-methyl-(tetrahydro-pyran-4-yl)-aminedihydrochloride (72) (reaction scheme 11)

(1) Methyl-[(R)-1-(4-nitro-phenyl)-ethyl]-(tetrahydro-pyran-4-yl)-amine(73)

(R)-α-Methyl-4-nitro-benzylammonium hydrochloride (Aldrich, 3 g, 15mmol), tetrahydropyridon (1.5 g, 15 mmol), pyridine (1.2 ml, 15 mmol)are dissolved in 100 ml DCE. Sodium triacetoxyborohydride (4 g, 19 mmol,95%) is added under stirring at room temperature; after 18 hoursreaction time formaldehyde (2.4 ml, 30% in water) is added followed bysodium triacetoxyborohydride (3 g, 14 mmol, 95%) and the mixture isagain stirred for 18 hours at room temperature. After addition of 2 mHCl the product is isolated by distribution between aqueous ammonia andEtOAc. The combined organic layers are washed with brine, dried overanhydrous sodium sulfate, filtered and evaporated under reducedpressure. The crude product (3.2 g, 82%) is used without furtherpurification. MS (ESI): 265 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm) 8.20 (d,2H), 7.55 (d, 2H), 4.0 (br m, 2H), 3.95 (br m, 1H), 3.3 (br m, 2H), 2.7(br m, 1H), 2.20 (s, 3H), 1.7 (br m, 4H), 1.40 (d, 3H)

(2) [(R)-1-(4-Amino-phenyl)-ethyl]-methyl-(tetrahydro-pyran-4-yl)-aminedihydrochloride (72)

Methyl-[(R)-1-(4-nitro-phenyl)-ethyl]-(tetrahydro-pyran-4-yl)-amine 73from above (3.2 g, 12 mmol) is stirred with RaNi (1 g) in 100 ml ofMeOH. Hydrazine monohydrate (3.2 ml) is added dropwise at roomtemperature and the reaction mixture is stirred for further 3 hours.After filtration and evaporation under reduced pressure the product isisolated by distribution between Et2O and brine, drying the organicphase with sodium sulfate, filtration and evaporation as yellow oil (2.6g, 92%).

MS (ESI): 235 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm) 7.15 (d, 2H), 6.65 (d,2H), 4.0 (br m, 2H), 3.7 (br m, 1H), 3.6 (NH2), 3.3 (br m, 2H), 2.7 (brm, 1H), 2.20 (s, 3H), 1.7 (br m, 4H), 1.30 (d, 3H)

Synthesis of the indole-2-carboxamides

The indole-2-carboxamides are Generally Prepared by a TBTU-MediatedCoupling of Appropriately Substituted indole-2-carboxylic Acids with theCorresponding Amines in the Presence of Hünig's Base (Reaction Scheme12).

Reaction Scheme 12:

An illustrative example is given below.

Example 1 4-Methoxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)piperidin-4-yl]-amide

A solution of 4-Methoxy-1H-indole-2-carboxylic acid (930 mg, 4.86 mmol),amine 5 (1.63 g, 4.86 mmol) and DIEA (2.5 ml, 14.58 mmol) in 20 ml ofDMF is treated with solid TBTU (1.56 g, 4.86 mmol). The mixture isstirred over night and then evaporated. The crude residue is dissolvedin EtOAc and washed twice with sodium bicarbonate (10%). The aqueouslayers are re-extracted with DCM, the combined organic layers are washedwith brine and dried over sodium sulfate. The crude product is thenpurified by chromatography on silicagel using DCM (saturated withammonia) and MeOH (from 0% to 2%).

Yield: 0.975 g (50%) of beige powder.

MS (ESI): 399.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.65 (s, 1H), 8.24(d, 1H), 7.28 (s, 1H), 7.09 (t, 1H), 7.0 (d, 1H), 6.5 (d, 1H), 3.75-3.9(m, 4H), 2.92-3.25 (m, 8H), 2.73 (m, 2H), 2.27 (m, 2H), 1.52-1.9 (m,12H).

The formation of the dihydrochlorides can be achieved by treatment of asolution of the free base in DCM or acetone with 2M HCl in ether at 0°C.

Example 2 4-Isopropoxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized analogously to Example 1 from4-Isopropoxy-1H-indole-2-carboxylic acid 74 (preparation see below) andamine 5.

MS (ESI): 427.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 8.24 (d, 1H), 7.22 (d,1H), 7.06 (t, 1H), 6.98 (d, 1H), 6.51 (d, 1H), 4.75 (m, 1H), 3.75 (m,1H), 2.99 (m, 2H), 2.53-2.64 (m, 6H), 2.39 (m, 2H), 2.02 (m, 2H), 1.77(m, 2H), 1.49-1.63 (m, 10H), 1.35 (d, 6H).

Synthesis of 4-Isopropoxy-1H-indole-2-carboxylic acid (74) (1) Step A:4-Hydroxy-1H-indole-2-carboxylic acid methyl ester (75)

To an ice cold solution of 4-Methyloxy-1H-indole-2-carboxylic acidmethyl ester (1 g, 4.87 mmol) in DCM (10 ml) is added BBr3 (1M in DCM,4.9 ml, 4.9 mmol). It is stirred for 1 hour and another equivalent (4.9ml) of BBr3 is added. After another hour, the mixture is poured on iceand the pH is adjusted to 7 with sodium bicarbonate. Extraction with DCMgave a yellow powder.

Yield: 0.82 g (88%). MS (ESI): 192.0 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.78 (br s, 1H), 9.73 (s, 1H), 7.21 (d, 1H), 7.05 (dd, 1H), 6.89 (d,1H), 6.4 (d, 1H), 3.86 (s, 3H).

(2) Step B: 4-Isopropoxy-1H-indole-2-carboxylic acid methyl ester (76)

DEAD (0.227 ml, 1.47 mmol) is slowly added to a solution of4-Hydroxy-1H-indole-2-carboxylic acid methyl ester 75 (200 mg, 1.05mmol), triphenylphosphine (384 mg, 1.47 mmol) and isopropanol (0.108 ml,1.43 mmol) in 2 ml of THF. Stirring is continued for 20 minutes and thesolvent is then evaporated. The crude mixture is purified bychromatography on silicagel using cyclohexane/EtOAc (9/1).

Yield: 89 mg (37%). MS (ESI): 234.0 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.89 (s, 1H), 7.26 (t, 1H), 7.07 (s, 1H), 6.98 (d, 1H), 6.54 (d, 1H),4.72 (m, 1H), 3.85 (s, 3H), 1.33 (d, 6H).

(3) Step C: 4-Isopropoxy-1H-indole-2-carboxylic acid (74)

4-Isopropoxy-1H-indole-2-carboxylic acid methyl ester 76 (114 mg, 0.49mmol) is dissolved in 5 ml of THF. A 2M-solution of LiOH in water (2.5ml, 5 mmol) is added and the mixture is stirred for 48 hours. Thesolvent is then evaporated and the residue is partitioned between waterand EtOAc. The water layer is acidified with HCl and extracted twicewith EtOAc. The combined organic layers are washed with brine, driedover anhydrous sodium sulfate, filtered and evaporated to give a yellowpowder.

Yield: 95 mg (89%). MS (ESI): 219.9 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.72 (br s, 1H), 7.14 (dd, 1H), 7.0 (m, 2H), 6.55 (d, 1H), 4.72 (m,1H), 1.33 (d, 6H).

Example 36b 4-Isopropoxy-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to Example 1 from4-Isopropoxy-1H-indole-2-carboxylic acid 74 (preparation see Example 2)and amine 21.

MS (ESI): 429.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.42 (s, 1H), 8.2 (d,1H), 7.19 (s, 1H), 7.02 (t, 1H), 6.94 (d, 1H), 6.48 (d, 1H), 4.72 (m,1H), 4.5 (br. s, 1H), 3.74 (m, 1H), 3.25-3.45 (m, 3H), 2.86 (m, 2H),2.71 (m, 2H), 2.37 (br. s, 4H), 2.0 (m, 4H), 1.73 (m, 4H), 1.54 (m, 2H),1.33 (d, 6H).

Example 4 4-Cyclopropylmethoxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized analogously to Example 1 from4-Cyclopropylmethoxy-1H-indole-2-carboxylic acid 77 (preparation seebelow) and amine 5.

MS (ESI): 439.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.43 (s, 1H), 8.2 (d,1H), 7.27 (s, 1H), 7.01 (t, 1H), 6.96 (d, 1H), 6.42 (d, 1H), 3.9 (d,2H), 3.72 (m, 1H), 2.87 (m, 2H), 2.52-2.62 (m, 6H), 2.37 (m, 2H), 2.0(m, 2H), 1.76 (m, 2H) 1.47-1.63 (m, 10H), 1.3 (m, 1H), 0.61 (m, 2H),0.37 (m, 2H).

Synthesis of 4-Cyclopropylmethoxy-1H-indole-2-carboxylic acid (77) (1)Step A: 4-Cyclopropylmethoxy-1H-indole-2-carboxylic acid (78)

DEAD (2.1 ml, 13.65 mmol) is slowly added to a solution of4-hydroxy-1H-indole-2-carboxylic acid ethyl ester 79 (2 g, 9.75 mmol),triphenylphosphine (3.58 g, 13.65 mmol) and cyclopropyl-methanol (1.05ml, 12.26 mmol) in 20 ml of THF, so that the temperature always remainedbelow 30° C. Stirring is continued for 2 hours and the solvent is thenevaporated.

The crude residue is purified by chromatography(cyclohexane:EtOAc/95:5). Yield: 1.17 g (46%).

MS (ESI): 260.1 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm) 8.85 (s, 1H), 7.4 (s,1H), 7.19 (t, 1H), 6.99 (d, 1H), 6.45 (d, 1H), 4.4 (q, 2H), 3.95 (d,2H), 1.41 (t, 3H), 1.34 (m, 1H), 0.66 (m, 2H), 0.4 (m, 2H).

(2) Step B: 4-Cyclopropylmethoxy-1H-indole-2-carboxylic acid (77)

The 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid ethyl ester 78obtained above is mixed with a 2M-solution of KOH in EtOH (16.9 ml, 33.8mmol) and stirred for 24 hours. The solvent is then evaporated and theresidue is partitioned between water and DCM. The water layer isacidified with HCl and extracted twice with EtOAc. The combined organiclayers are washed with brine, dried over anhydrous sodium sulfate,filtered and evaporated to give a white powder.

Yield: 1.02 g (99%).

MS (ESI): 232.2 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm) 8.84 (s, 1H), 7.55 (s,1H), 7.26 (t, 1H), 7.01 (d, 1H), 6.48 (d, 1H), 3.97 (d, 2H), 1.36 (m,1H), 0.66 (m, 2H), 0.41 (m, 2H).

Example 5 4-Cyclopropylmethoxy-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to Example 1 from4-Cyclopropylmethoxy-1H-indole-2-carboxylic acid 77 (preparation seeExample 4) and amine 21.

MS (ESI): 441.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.43 (s, 1H), 8.2 (d,1H), 7.27 (s, 1H), 7.01 (t, 1H), 6.96 (d, 1H), 6.42 (d, 1H), 4.49 (d,1H), 3.91 (d, 2H), 3.72 (m, 1H), 3.4 (m, 1H), 2.86 (m, 2H), 2.71 (m,2H), 2.38 (br. s, 4H) 1.99 (m, 4H), 1.75 (m, 2H), 1.68 (m, 2H), 1.54 (m,2H), 1.22-1.42 (m, 3H), 0.61 (m, 2H), 0.37 (m, 2H).

Example 6 4-Cyclopropylmethoxy-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-cyclopropylmethoxy-1H-indole-2-carboxylic acid, 77 (see example 4) andamine 50.

MS (ESI): 455.4 [M+H]⁺, 1H-NMR (CD₃OD): δ (ppm) 7.14 (s, 1H), 6.98 (t,1H), 6.89 (d, 1H), 6.33 (d, 1H), 3.83 (d, 2H), 3.75 (m, 1H), 3.45 (m,1H), 2.93 (m, 1H), 2.77 (m, 1H), 2.68 (m, 3H), 2.39 (m, 1H), 2.26 (m,2H), 2.11 (m, 2H), 1.95 (m, 1H), 1.79 (m, 2H), 1.73 (m, 2H), 1.55 (m,2H) 1.42 (m, 2H), 1.21 (m, 1H), 0.93 (d, 3H), 0.51 (m, 2H), 0.28 (m,2H).

Example 7 4-Cyclopropylmethoxy-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-cyclopropylmethoxy-1H-indole-2-carboxylic acid, 77 (see example 4) andamine 56.

MS (ESI): 469.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.44 (s, 1H), 8.2 (d,1H), 7.27 (s, 1H), 7.01 (t, 1H), 6.95 (d, 1H), 6.41 (d, 1H), 4.44 (d,1H), 3.91 (d, 2H), 3.74 (m, 1H), 2.61-2.95 (m, 6H), 2.04-2.38 (m, 4H),1.85-1.97 (m, 2H), 1.66-1.81 (m, 3H), 1.45-1.63 (m, 2H), 1.2-1.43 (m,3H), 0.91 (d, 3H), 0.87 (d, 3H), 0.61 (m, 2H), 0.37 (m, 2H).

Example 8 4-Isobutoxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized analogously to Example 1 from4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see below) andamine 5.

MS (ESI): 441.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.45 (s, 1H), 8.21(d, 1H), 7.23 (d, 1H), 7.03 (t, 1H), 6.97 (d, 1H), 6.46 (d, 1H), 3.84(d, 2H), 3.75 (m, 1H), 2.99 (m, 1H), 2.53-2.67 (m, 6H), 2.41 (m, 2H),2.1 (m, 1H), 2.02 (m, 2H) 1.78 (m, 2H), 1.48-1.62 (m, 8H), 1.06 (d, 6H).

Synthesis of 4-Isobutoxy-1H-indole-2-carboxylic acid (80) (1) Step A:4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (79)

To a solution of 4-Benzyloxy-1H-indole-2-carboxylic acid ethyl ester (29g, 98.2 mmol) in a mixture of MeOH (750 ml) and DCM (500 ml) is added 1gram of Pd/C (10%). It is hydrogenated under normal pressure for 24hours. After filtration and evaporation a white powder is obtained.

Yield: 19.63 g (97%). MS (ESI): 206.0 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.72 (br s, 1H), 9.69 (s, 1H), 7.2 (s, 1H), 7.05 (t, 1H), 6.98 (d, 1H),6.38 (d, 1H), 4.33 (q, 2H), 1.32 (t, 3H).

(2) Step B: 4-Isobutoxy-1H-indole-2-carboxylic acid ethyl ester (81)

DEAD (10.2 ml, 65.28 mmol) is slowly added to a solution of4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester 79 (9.57 g, 46.63mmol), triphenylphosphine (17.12 g, 65.28 mmol) and isobutanol (5.9 ml,63.42 mmol) in 100 ml of THF, so that the temperature always remainedbelow 30° C. Stirring is continued for 3 hours and the solvent is thenevaporated. The crude mixture is purified by chromatography on silicagelusing first cyclohexane as eluent, then increasing amounts of EtOAc(from 5% to 50%).

Yield: 8 g (65%).

MS (ESI): 260.0 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 8.86 (s, 1H), 7.36 (s,1H), 7.22 (t, 1H), 6.99 (d, 1H), 6.48 (d, 1H), 4.4 (q, 2H), 3.86 (d,2H), 2.2 (m, 1H), 1.42 (t, 3H), 1.09 (d, 6H).

(3) Step C: 4-Isobutoxy-1H-indole-2-carboxylic acid (80)

4-Isobutoxy-1H-indole-2-carboxylic acid ethyl ester 81 (5.2 g, 19.9mmol) is mixed with a 1M-solution of KOH in EtOH (99.5 ml, 99.5 mmol)and stirred for 24 hours. The solvent is then evaporated and the residueis partitioned between water and ether. The water layer is acidifiedwith HCl and extracted twice with ether. The combined organic layers arewashed with brine, dried over anhydrous sodium sulfate, filtered andevaporated to give a beige powder.

Yield: 4.32 g (93%). MS (ESI): 234.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.74 (br s, 1H), 7.13 (dd, 1H), 7.06 (s, 1H), 7.0 (d, 1H), 6.49 (d,1H), 3.85 (d, 2H), 3.35 (br s, 1H), 2.1 (m, 1H), 1.03 (d, 6H).

Example 9 4-Isobutoxy-1H-indole-2-carboxylic acid[1-(2-piperidin-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized analogously to Example 1 from4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8)and amine 1.

MS (ESI): 427.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.45 (s, 1H), 8.21(d, 1H), 7.23 (d, 1H), 7.03 (t, 1H), 6.96 (d, 1H), 3.84 (d, 2H), 3.75(m, 1H), 2.88 (m, 2H), 2.38 (m, 8H), 2.1 (m, 1H), 2.02 (m, 2H), 1.78 (m,2H), 1.32-1.63 (m, 9H), 1.07 (d, 6H).

Example 10 4-Isobutoxy-1H-indole-2-carboxylic acid{1-[2-(RS)-2-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to Example 1 from4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8)and amine 10.

MS (ESI): 441.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.43 (s, 1H), 8.19(d, 1H), 7.22 (d, 1H), 7.03 (t, 1H), 6.97 (d, 1H), 6.45 (d, 1H), 3.85(d, 2H), 3.75 (m, 1H), 2.65-2.93 (m, 7H), 2.05-2.43 (m, 5H), 2.01 (m,2H), 1.78 (m, 2H), 1.1-1.62 (m, 6H), 1.06 (d, 6H), 1.01 (d, 3H).

Example 11 4-Isobutoxy-1H-indole-2-carboxylic acid{1-[2-(4-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to Example 1 from4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8)and amine 7.

MS (ESI): 441.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.44 (s, 1H), 8.2 (d,1H), 7.22 (d, 1H), 7.02 (t, 1H), 6.96 (d, 1H), 6.46 (d, 1H), 3.86 (d,2H), 3.75 (m, 1H), 2.86 (m, 4H), 2.4 (br s, 4H), 2.11 (m, 1H), 2.02 (m,2H), 1.9 (m, 2H), 1.79 (m, 2H), 1.55 (m, 4H), 1.3 (m, 1H), 1.11 (m, 2H),1.06 (d, 6H), 0.88 (d, 3H).

Example 12 4-Isobutoxy-1H-indole-2-carboxylic acid{1-[2-(2,6-dimethyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to Example 1 from4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8)and amine 27.

MS (ESI): 455.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 8.2 (d, 1H), 7.22 (d,1H), 7.04 (t, 1H), 6.96 (d, 1H), 6.45 (d, 1H), 3.85 (d, 2H), 3.75 (m,1H), 2.87 (m, 2H), 2.7 (m, 2H), 2.43 (m, 2H), 2.32 (m, 2H), 2.1 (m, 2H),2.03 (m, 2H), 1.78 (m, 2H), 1.45-1.65 (m, 5H), 1.0-1.35 (m, 16H).

Example 13 4-Isobutoxy-1H-indole-2-carboxylic acid{1-[2-((R)-3-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to Example 1 from4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8)and amine 12.

MS (ESI): 443.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.45 (s, 1H), 8.21(d, 1H), 7.23 (s, 1H), 7.04 (t, 1H), 6.97 (d, 1H), 6.45 (d, 1H), 4.54(d, 1H), 3.84 (d, 1H), 3.75 (m, 1H), 3.42 (m, 1H), 2.62-2.93 (m, 2H),2.49 (br s, 4H), 2.1 (m, 1H), 2.0 (m, 2H), 1.3-1.9 (m, 11H), 1.06 (d,6H).

Example 14 4-Isobutoxy-1H-indole-2-carboxylic acid{1-[2-((S)-3-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is obtained by preparative separation of racemic materialusing a chiral HPLC stationary phase (CHIRALCEL OJ-H 1170). The absolutestereochemistry is assigned by comparison with the enantiomericallydefined (R)-isomer of example 13.

Example 15 4-Isobutoxy-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to Example 1 from4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8)and amine 21.

MS (ESI): 443.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.45 (s, 1H), 8.2 (d,1H), 7.23 (d, 1H), 7.04 (t, 1H), 6.97 (d, 1H), 6.45 (d, 1H), 4.5 (d,1H), 3.85 (d, 2H) 3.74 (m, 1H), 3.41 (m, 1H), 2.88 (m, 2H), 2.71 (m,2H), 2.38 (m, 4H), 2.1 (m, 1H), 2.0 (m, 4H), 1.76 (m, 2H), 1.68 (m, 2H),1.55 (m, 2H), 1.35 (m, 2H), 1.06 (d, 6H).

Example 16 4-Isobutoxy-1H-indole-2-carboxylic acid{1-[2-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to Example 1 from4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8)and amine 24.

MS (ESI): 469.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 8.23 (d, 1H), 7.72 (s,1H), 6.9-7.1 (m, 2H), 6.46 (d, 1H), 4.57 (br s, 1H), 3.85 (d, 2H), 3.77(m, 1H), 3.2-3.7 (br m, 4H), 2.94 (m, 2H), 2.75 (m, 2H), 2.56 (m, 2H),1.5-2.25 (m, 15H), 1.06 (d, 6H).

Example 17 4-Isobutoxy-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-isobutoxy-1H-indole-2-carboxylic acid, 80 (see example 8) and amine50.

MS (ESI): 457.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.43 (s, 1H), 8.19(d, 1H), 7.22 (d, 1H), 7.02 (t, 1H), 6.96 (d, 1H), 6.44 (d, 1H), 4.47(d, 1H), 3.84 (d, 2H), 3.73 (m, 1H), 3.37 (m, 1H), 2.6-2.95 (m, 5H),2.05-2.38 (m, 6H), 1.92 (m, 1H), 1.76 (m, 2H), 1.69 (m, 2H), 1.2-1.65(m, 4H), 1.05 (d, 6H), 0.92 (d, 3H).

Example 18 4-Isobutoxy-1H-indole-2-carboxylic acid[4-(2-azepan-1-yl-ethyl)-phenyl]amide

This compound is synthesized analogously to Example 1 from4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8)and amine 70.

MS (ESI): 434.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.65 (s, 1H), 10.07(s, 1H), 7.67 (d, 2H), 7.48 (d, 1H), 7.18 (d, 2H), 7.08 (t, 1H), 7.01(d, 1H), 6.49 (d, 1H), 3.88 (d, 2H), 2.57-2.62 (m, 8H), 2.13 (m, 2H),1.48-1.63 (m, 8H), 1.08 (d, 6H).

Example 19

4-Isobutoxy-1H-indole-2-carboxylic acid(4-{[methyl-(tetrahydro-pyran-4-yl)-amino]-methyl}-cyclohexyl)-amide

This compound is synthesized analogously to Example 1 from4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8)and trans-4-Amino-cyclohexylmethyl)-methyl-(tetrahydro-pyran-4-yl)-amine(WO2000068203)

MS (ESI): 442.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.43 (s, 1H), 8.18(d, 1H), 7.23 (s, 1H), 7.03 (t, 1H), 6.96 (d, 1H), 6.45 (d, 1H),3.82-3.93 (m, 4H), 3.74 (m, 1H), 3.22-3.31 (m, 2H), 2.7 (s, 3H), 2.45(m, 1H), 2.18 (m, 4H), 2.11 (m, 1H), 1.85 (m, 4H), 1.6 (m, 2H), 1.2-1.48(m, 5H), 1.06 (d, 6H).

Example 20 4-Isobutoxy-1H-indole-2-carboxylic acid(4-{[methyl-(tetrahydro-pyran-4-yl)-amino]-methyl}-phenyl)-amide

This compound is synthesized analogously to Example 1 from4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8)and (4-Amino-benzyl)-methyl-(tetrahydro-pyran-4-yl)-amine (WO9932468).

MS (ESI): 436.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.65 (s, 1H), 10.12(s, 1H), 7.74 (d, 2H), 7.5 (s, 1H), 7.27 (d, 2H), 7.09 (t, 1H), 7.02 (d1H), 6.5 (d, 1H), 3.84-3.94 (m, 4H), 3.52 (s, 2H), 3.22-3.32 (m, 2H),2.6 (m, 1H), 2.08-2.2 (m, 4H), 1.72 (m, 2H), 1.53 (m, 2H), 1.07 (d, 6H).

Example 21 4-Isobutoxy-1H-indole-2-carboxylic acid(4-{(R)-1-[methyl-(tetrahydro-pyran-4-yl)-amino]-ethyl}-phenyl)-amide

This compound is synthesized analogously to Example 1 from4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8)and amine 72.

MS (ESI): 450.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.66 (s, 1H), 10.12(s, 1H), 7.73 (d, 2H), 7.5 (d, 1H), 7.3 (d, 2H), 7.09 (t, 1H), 7.02 (d,1H), 6.5 (d, 1H), 3.76-3.91 (m, 5H), 3.1-3.33 (m, 2H), 2.68 (m, 1H),2.04-2.2 (m, 4H), 1.36-1.68 (m, 4H), 1.28 (d, 3H), 1.08 (d, 6H).

Example 22 4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized analogously to Example 1 from4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid 82 (preparation seebelow) and amine 5.

MS (ESI): 453.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.43 (s, 1H), 8.21(d, 1H), 7.19 (s, 1H), 7.03 (t, 1H), 6.96 (d, 1H), 6.47 (d, 1H), 4.05(d, 2H), 3.74 (m, 1H), 2.86 (m, 2H), 2.78 (m, 1H), 2.55-2.7 (m, 6H), 2.4(m, 2H), 1.83-2.18 (m, 8H), 1.76 (m, 2H) 1.47-1.63 (m, 10H).

Synthesis of 4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid (82) (1)Step A: 4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid (83)

DEAD (2.1 ml, 13.65 mmol) is slowly added to a solution of4-hydroxy-1H-indole-2-carboxylic acid ethyl ester 79 (2 g, 9.75 mmol),triphenylphosphine (3.58 g, 13.65 mmol) and cyclobutyl-methanol (1.25ml, 12.26 mmol) in 20 ml of THF, so that the temperature always remainedbelow 30° C. Stirring is continued for 2 hours and the solvent is thenevaporated. The crude residue is purified by chromatography(cyclohexane:EtOAc/95:5).

Yield: 1.86 g (70%). MS (ESI): 274.2 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm)8.83 (s, 1H), 7.35 (s, 1H), 7.21 (t, 1H), 6.98 (d, 1H), 6.49 (d, 1H),4.4 (q, 2H), 4.07 (d, 2H), 2.85 (m, 1H), 2.17 (m, 2H), 1.95 (m, 4H),1.42 (t, 3H).

(2) Step B: 4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid (82)

The 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid ethyl ester 83obtained above is mixed with a 2M-solution of KOH in EtOH (16.9 ml, 33.8mmol) and stirred for 24 hours. The solvent is then evaporated and theresidue is partitioned between water and DCM. The water layer isacidified with HCl and extracted twice with EtOAc. The combined organiclayers are washed with brine, dried over anhydrous sodium sulfate,filtered and evaporated to give a white powder.

Yield: 1.65 g (99%). MS (ESI): 246.3 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm)11.74 (br. s, 1H), 7.14 (t, 1H), 7.03 (s, 1H), 6.99 (d, 1H), 6.51 (d,1H), 4.05 (d, 2H), 2.8 (m, 1H), 2.11 (m, 2H), 1.93 (m, 4H).

Example 23 4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid{1-[2-(3-(R)-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to Example 1 from4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid 82 (preparation seeExample 22) and amine 12.

MS (ESI): 455.4 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.43 (s, 1H), 8.22(d, 1H), 7.19 (s, 1H), 7.03 (t, 1H), 6.97 (d, 1H), 6.47 (d, 1H), 4.56(br s, 1H), 4.05 (d, 2H), 3.75 (m, 1H), 3.43 (m, 1H), 2.88 (m, 3H), 2.78(m, 1H), 2.68 (m, 1H), 2.42 (br. s, 4H), 1.83-2.2 (m, 8H), 1.77 (m, 4H),1.56 (m, 4H), 1.38 (m, 2H).

Example 24 4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to Example 1 from4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid 82 (preparation seeExample 22) and amine 21.

MS (ESI): 455.4 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.43 (s, 1H), 8.21(d, 1H), 7.19 (s, 1H), 7.03 (t, 1H), 6.96 (d, 1H), 6.47 (d, 1H), 4.49(s, 1H), 4.05 (d, 2H), 3.73 (m, 1H), 3.41 (m, 1H), 2.87 (m, 2H), 2.78(m, 1H), 2.7 (m, 2H), 2.38 (m, 4H) 2.14 (m, 2H), 1.83-2.07 (m, 8H), 1.76(m, 2H), 1.68 (m, 2H), 1.54 (m, 2H), 1.35 (m, 2H).

Example 25 4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-cyclobutylmethoxy-1H-indole-2-carboxylic acid, 82 (see example 22) andamine 14.

MS (ESI): 469.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.44 (s, 1H), 8.21(d, 1H), 7.19 (s, 1H), 7.03 (t, 1H), 6.96 (d, 1H), 6.46 (d, 1H), 4.48(d, 1H), 4.04 (d, 2H), 3.73 (br m, 1H), 2.64-2.97 (m, 6H), 2.37 (m, 4H),2.05-2.2 (m, 2H), 1.81-2.05 (m, 7H), 1.65-1.81 (m, 3H), 1.46-1.65 (m,3H), 1.27-1.46 (m, 2H), 0.86 (d, 3H).

Example 26 4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid{1-[2-(3-(R)-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to Example 1 from4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid 82 (preparation seeExample 22) and amine 24.

MS (ESI): 481.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.44 (s, 1H), 8.21(d, 1H), 7.19 (s, 1H), 7.03 (t, 1H), 6.96 (d, 1H), 6.47 (d, 1H), 4.31(br s, 1H), 4.04 (d, 2H), 3.8 (br. S, 1H), 3.74 (m, 1H), 2.89 (m, 2H),2.78 (m, 1H), 2.42 (br. m, 6H), 1.7-2.2 (m, 16H), 1.56 (m, 4H).

Example 27 4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-cyclobutylmethoxy-1H-indole-2-carboxylic acid, 82 (see example 22) andamine 50.

MS (ESI): 469.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.45 (s, 1H), 8.21(d, 1H), 7.18 (s, 1H), 7.03 (t, 1H), 6.96 (d, 1H), 6.46 (d, 1H), 4.46(d, 1H), 4.05 (d, 2H), 3.74 (m, 1H), 3.36 (m, 1H), 2.6-2.95 (m, 6H),2.04-2.4 (m, 7H), 1.83-2.0 (m, 4H), 1.64-1.81 (m, 4H), 1.45-1.63 (m,2H), 1.23-1.42 (m, 2H), 0.92 (d, 3H).

Example 28 4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-cyclobutylmethoxy-1H-indole-2-carboxylic acid, 82 (see example 22) andamine 56.

MS (ESI): 483.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.46 (s, 1H), 8.22(d, 1H), 7.19 (s, 1H), 7.03 (t, 1H), 6.96 (d, 1H), 6.46 (d, 1H), 4.44(d, 1H), 4.04 (d, 2H), 3.74 (m, 1H), 2.6-2.95 (m, 7H), 2.33 (m, 1H),2.24 (m, 1H), 2.02-2.19 (m, 4H), 1.82-2.01 (m, 6H), 1.66-1.81 (m, 3H),1.45-1.64 (m, 2H), 1.2-1.43 (m, 2H), 0.91 (d, 3H), 0.87 (d, 3H).

Example 29 4-(3-Methyl-butyloxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized analogously to Example 1 from4-(3-methyl-butyloxy)-1H-indole-2-carboxylic acid (84) (preparation seebelow) and amine 21.

Yield: 110 mg (43%). MS (ESI): 457 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.4 (s, 1H), 10.5-10.8 (br, 2H), 8.58 (d, 1H), 7.22 (s, 1H), 7.05 (dd,1H), 6.95 (d, 1H), 6.48 (d, 1H), 4.1 (t, 2H), 3.4-3.75 (m, 9H), 2.9-3.2(m, 4H), 1.65-2.1 (m, 11H), 0.95 (d, 6H).

Synthesis of 4-(3-methyl-butyloxy)-1H-indole-2-carboxylic acid (84)

This compound is synthesized analogously to (85) from3-methyl-butan-1-ol.

Yield: 0.54 g (100%). MS (ESI): 246 [M−H]⁻.

Example 30 4-Cyclopentylmethoxy-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to Example 1 from4-Cyclopentylmethoxy-1H-indole-2-carboxylic acid 86 (preparation seebelow) and amine 21.

MS (ESI): 469.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.42 (s, 1H), 8.19(d, 1H), 7.18 (s, 1H), 7.01 (t, 1H), 6.95 (d, 1H), 6.45 (d, 1H), 4.48(br. s, 1H), 3.93 (d, 2H), 3.72 (m, 1H), 3.4 (m, 1H), 3.15 (br.s, 1H),2.86 (m, 2H), 2.7 (m, 2H), 2.37 (m, 4H) 1.99 (m, 4H), 1.25-1.88 (m,16H).

Synthesis of 4-Cyclopentylmethoxy-1H-indole-2-carboxylic acid (86) (1)Step A: 4-Cyclopentylmethoxy-1H-indole-2-carboxylic acid ethyl ester(87)

DEAD (5.3 ml, 34.1 mmol) is slowly added to a solution of4-hydroxy-1H-indole-2-carboxylic acid ethyl ester 79 (2 g, 24.36 mmol),triphenylphosphine (8.95 g, 34.1 mmol) and cyclopentyl-methanol (3.58ml, 33.13 mmol) in 30 ml of THF, so that the temperature always remainedbelow 30° C. Stirring is continued for 2 hours and the solvent is thenevaporated. The crude residue is purified by chromatography(cyclohexane:EtOAc/90:10).

Yield: 3.88 g (55%). MS (ESI): 288.3 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm)8.86 (br. s, 1H), 7.35 (s, 1H), 7.21 (t, 1H), 6.98 (d, 1H), 6.48 (d,1H), 4.4 (q, 2H), 3.98 (d, 2H), 2.47 (m, 1H), 1.89 (m, 2H), 1.65 (m,4H), 1.42 (t, 3H and overlapping m, 2H).

(2) Step B: 4-Cyclopentylmethoxy-1H-indole-2-carboxylic acid (86)

The 4-cyclopentylmethoxy-1H-indole-2-carboxylic acid ethyl ester 87obtained above is mixed with a 2M-solution of KOH in EtOH (33.8 ml, 67.6mmol) and stirred for 24 hours. The solvent is then evaporated and theresidue is partitioned between water and ether. The water layer isacidified with HCl and extracted twice with EtOAc. The combined organiclayers are washed with brine, dried over anhydrous sodium sulfate,filtered and evaporated to give a white powder.

Yield: 2.55 g (73%). MS (ESI): 260.1 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.73 (br. s, 1H), 7.12 (t, 1H), 7.02 (s, 1H), 6.98 (d, 1H), 6.5 (d,1H), 3.96 (d, 2H), 2.39 (m, 1H), 1.82 (m, 2H), 1.6 (m, 4H), 1.4 (m, 2H).

Example 31 4-(1,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized analogously to Example 1 from4-(1,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid 88 (preparation seebelow) and amine 5.

MS (ESI): 455.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.4 (s, 1H), 8.2 (d,1H), 7.18 (d, 1H), 7.02 (dd, 1H), 6.93 (d, 1H), 6.47 (d, 1H), 4.37 (m,1H), 3.74 (m, 1H), 2.88 (m, 2H), 2.52-2.62 (m, 6H), 2.37 (m, 2H),1.89-2.06 (m, 3H), 1.75 (m, 2H), 1.46-1.62 (m, 10H), 1.24 (d, 3H), 1.0(m, 6H).

Synthesis of 4-(1,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid (88)(1) Step A: 4-(1,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid ethylester (89)

DEAD (5.3 ml, 34.1 mmol) is slowly added to a solution of4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester 79 (5 g, 24.36 mmol),triphenylphosphine (8.95 g, 34.1 mmol) and 3-Methyl-butan-2-ol (3.58 ml,33.13 mmol) in 50 ml of THF, so that the temperature always remainedbelow 30° C. Stirring is continued for 3 days and the solvent is thenevaporated. The crude mixture is purified by chromatography on silicagelusing first cyclohexane as eluent, then increasing amounts of EtOAc(from 5% to 50%).

Yield: 2.4 g (36%). MS (ESI): 276.3 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm) 8.9(br s, 1H), 7.35 (s, 1H), 7.2 (dd, 1H), 6.96 (d, 1H), 6.5 (d, 1H), 4.4(q, 2H), 4.34 (t, 1H), 2.03 (m, 1H), 1.42 (t, 3H), 1.31 (d, 3H), 1.04(m, 6H).

(2) Step B: 4-(1,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid (88)

4-(1,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid ethyl ester 89 (2.4g, 8.72 mmol) is mixed with a 1M-solution of KOH in EtOH (43.6 ml, 87.2mmol) and stirred for 48 hours. The solvent is then evaporated and theresidue is partitioned between water and ether. The water layer isacidified with HCl and extracted twice with ether. The combined organiclayers are washed with brine, dried over anhydrous sodium sulfate,filtered and evaporated to give a beige powder.

Yield: 2.14 g (99%). MS (ESI): 248.1 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)8.92 (br s, 1H), 7.52 (s, 1H), 7.27 (m, 1H), 6.99 (d, 1H), 6.51 (d, 1H),4.34 (m, 1H), 2.02 (m, 1H), 1.33 (d, 3H), 1.04 (m, 6H).

Example 32 4-(2,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized analogously to Example 1 from4-(2,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid 85 (preparation seebelow) and amine 5.

MS (ESI): 455.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.47 (s, 1H), 8.25(d, 1H), 7.25 (d, 1H), 7.06 (t, 1H), 6.99 (d, 1H), 6.48 (d, 1H),3.72-3.84 (m, 3H), 2.92 (m, 1H), 2.54-2.63 (m, 6H), 2.41 (m, 2H), 2.04(m, 2H), 1.79 (m, 2H), 1.5-1.65 (m, 11H), 1.1 (s, 9H).

Synthesis of 4-(2,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid (85)(1) Step A: 4-(2,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid methylester (90)

DEAD (0.414 ml, 2.66 mmol) is slowly added to a solution of4-Hydroxy-1H-indole-2-carboxylic acid methyl ester 75 (363 mg, 1.9mmol), triphenylphosphine (698 mg, 2.66 mmol) and2,2-Dimethyl-propan-1-ol (228 mg, 2.58 mmol) in 8 ml of THF. Stirring iscontinued for 20 hours and the solvent is then evaporated. The crudemixture is purified by chromatography on silicagel usingcyclohexane/EtOAc (9/1).

Yield: 271 mg (55%). MS (ESI): 261.9 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm) 8.9(br s, 1H), 7.39 (s, 1H), 7.23 (dd, 1H), 7.0 (d, 1H), 6.47 (d, 1H), 3.95(s, 3H), 3.74 (s, 2H), 1.0 (s, 9H).

(2) Step B: 4-(2,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid (85)

4-(2,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid methyl ester 90(270 mg, 1.03 mmol) is dissolved in 20 ml of THF. A 2M-solution of LiOHin water (5.2 ml, 11 mmol) is added and the mixture is stirred for 48hours. The solvent is then evaporated and the residue is partitionedbetween water and ether. The water layer is acidified with HCl andextracted twice with EtOAc. The combined organic layers are washed withbrine, dried over anhydrous sodium sulfate, filtered and evaporated togive a yellow powder.

Yield: 230 mg (90%). MS (ESI): 248.0 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.75 (br s, 1H), 7.13 (dd, 1H), 7.08 (s, 1H), 7.0 (d, 1H), 6.49 (d,1H), 4.74 (s, 2H), 1.07 (s, 9H).

Example 33 4-(4-Methyl-pentyloxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized analogously to Example 1 from4-(4-methyl-pentyloxy)-1H-indole-2-carboxylic acid (91) (preparation seebelow) and amine 21.

Yield: 145 mg (70%). MS (ESI): 471 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 10.4-10.7 (br, 2H), 8.58 (d, 1H), 7.25 (s, 1H), 7.05 (dd,1H), 6.95 (d, 1H), 6.45 (d, 1H), 3.95-4.2 (m, 4H), 2.95-3.8 (m, 12H),1.7-2.1 (m, 10H), 1.6 (m, 2H), 1.35 (m, 2H), 0.9 (d, 6H).

Synthesis of 4-(4-methyl-pentyloxy)-1H-indole-2-carboxylic acid (91)

This compound is synthesized analogously to (85) from4-methyl-pentan-1-ol. Yield: 0.61 g (94%). MS (ESI): 260 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 12.8 (s, 1H), 11.65 (s, 1H), 7.1 (dd, 1H), 7.0 (s,1H), 6.98 (d, 1H), 6.48 (d, 1H), 4.05 (t, 2H), 1.77 (t, 2H), 1.63 (m,1H), 1.35 (m, 2H), 0.9 (d, 6H).

Example 34 4-(3,3-Dimethyl-butoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized analogously to Example 1 from4-(3,3-dimethyl-butoxy)-1H-indole-2-carboxylic acid (92) (preparationsee below) and amine 21.

Yield: 60 mg (24%). MS (ESI): 471 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.4(s, 1H), 10.5 (br, 1H), 8.58 (d, 1H), 7.17 (s, 1H), 7.0-7.1 (m, 2H), 6.5(d, 1H), 4.2 (m, 2H), 4.15 (m, 1H), 3.85 (m, 1H), 3.65 (m, 4H), 3.1-3.5(m, 8H), 2.0-2.2 (m, 6H), 1.75-1.85 (m, 4H), 1.03 (s, 9H).

Synthesis of 4-(3,3-Dimethyl-butoxy)-1H-indole-2-carboxylic acid (92)

This compound is synthesized analogously to (85) from3,3-dimethyl-butan-1-ol. Yield: 1.1 g (100%). MS (ESI): 260 [M−H]⁻,1H-NMR (DMSO-d₆): δ (ppm) 12.8 (s, 1H), 11.65 (s, 1H), 7.12 (dd, 1H),6.98 (s, 1H), 6.95 (d, 1H), 6.52 (d, 1H), 4.13 (t, 2H), 1.75 (t, 2H),1.0 (s, 9H).

Example 35 4-(Furan-2-ylmethoxy)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized analogously to Example 1 from4-(furan-2-ylmethoxy)-1H-indole-2-carboxylic acid 93 (preparation seebelow) and amine 5.

MS (ESI): 465.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.48 (s, 1H), 8.13(d, 1H), 7.71 (s, 1H), 7.23 (s, 1H), 7.06 (t, 1H), 7.0 (d, 1H), 6.63 (m,2H), 6.48 (s, 1H), 5.13 (s, 2H), 3.72 (m, 1H), 2.86 (m, 2H), 2.5-2.6 (m,6H), 2.36 (m, 2H), 2.0 (m, 2H), 1.74 (m, 2H) 1.45-1.6 (m, 10H).

Synthesis of 4-(furan-2-ylmethoxy)-1H-indole-2-carboxylic acid (93) (1)Step A: 4-(furan-2-ylmethoxy)-1H-indole-2-carboxylic acid ethyl ester(94)

DEAD (2.1 ml, 13.65 mmol) is slowly added to a solution of4-hydroxy-1H-indole-2-carboxylic acid ethyl ester 79 (2 g, 9.75 mmol),triphenylphosphine (3.58 g, 13.65 mmol) and furan-2-yl-methanol (1.18ml, 12.26 mmol) in 10 ml of THF, so that the temperature always remainedbelow 30° C. Stirring is continued for 2 hours and the solvent is thenevaporated. The crude residue is purified by chromatography(cyclohexane:EtOAc/95:5).

Yield: 0.76 g (27%).

(2) Step B: 4-(furan-2-ylmethoxy)-1H-indole-2-carboxylic acid (93)

The 4-(furan-2-ylmethoxy)-1H-indole-2-carboxylic acid ethyl ester 94obtained above is mixed with a 1M-solution of KOH in EtOH (13.3 ml, 13.3mmol) and stirred for 24 hours. The solvent is then evaporated and theresidue is partitioned between water and ether. The water layer isacidified with HCl and extracted twice with EtOAc. The combined organiclayers are washed with brine, dried over anhydrous sodium sulfate,filtered and evaporated to give a white powder.

Yield: 0.329 mg (48%). 1H-NMR (DMSO-d₆): δ (ppm) 12.79 (br s, 1H), 11.73(s, 1H), 7.69 (s, 1H), 7.14 (t, 1H), 7.02 (d, 1H), 6.98 (s, 1H), 6.68(d, 1H), 6.61 (s, 1H), 6.47 (s, 1H), 5.16 (s, 2H).

Example 36 4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized analogously to Example 1 from4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid 95 (preparation seebelow) and amine 5.

MS (ESI): 465.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.46 (s, 1H), 8.14(d, 1H), 7.82 (s, 1H), 7.68 (s, 1H), 7.22 (s, 1H), 7.06 (t, 1H), 6.99(d, 1H), 6.62 (s, 1H), 6.6 (d, 1H), 5.03 (s, 2H), 3.72 (m, 1H), 2.87 (m,2H), 2.52-2.62 (m, 6H), 2.37 (m, 2H), 2.0 (m, 2H), 1.75 (m, 2H)1.45-1.62 (m, 10H).

Synthesis of 4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid (95) (1)Step A: 4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid ethyl ester(96)

DEAD (2.1 ml, 13.65 mmol) is slowly added to a solution of4-hydroxy-1H-indole-2-carboxylic acid ethyl ester 79 (2 g, 9.75 mmol),triphenylphosphine (3.58 g, 13.65 mmol) and furan-3-yl-methanol (1.18ml, 12.26 mmol) in 10 ml of THF, so that the temperature always remainedbelow 30° C. Stirring is continued for 2 hours and the solvent is thenevaporated. The crude residue is triturated with ether and the whiteprecipitate is filtered off. It contained mainly product. The motherliquor is purified by chromatography (cyclohexane:EtOAc/95:5) andcombined with the first precipitate. Yield: 3 g (>100%).

(2) Step B: 4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid (95)

The 4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid ethyl ester 96obtained above is mixed with a 1M-solution of KOH in EtOH (35 ml, 35mmol) and stirred for 24 hours. The solvent is then evaporated and theresidue is partitioned between water and ether. The water layer isacidified with HCl and extracted twice with EtOAc. The combined organiclayers are washed with brine, dried over anhydrous sodium sulfate,filtered and evaporated to give a white powder.

Yield: 1.63 g (65%). MS (ESI): 258.0 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)12.79 (br s, 1H), 11.71 (s, 1H), 7.81 (s, 1H), 7.67 (s, 1H), 7.13 (m,1H), 7.01 (m, 2H), 6.62 (m, 2H), 5.07 (s, 2H).

Example 37 4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid 95 (see example 36)and amine 21.

MS (ESI): 467 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.48 (s, 1H), 8.13 (d,1H), 7.81 (s, 1H), 7.68 (t, 1H), 7.22 (d, 1H), 7.06 (t, 1H), 6.98 (d,1H), 6.62 (s, 1H), 6.6 (d, 1H), 5.03 (s, 2H), 4.48 (d, 1H), 3.73 (m,1H), 3.4 (m, 1H), 2.86 (m, 2H), 2.7 (m, 2H), 2.36 (br. s, 4H) 2.0 (m,4H), 1.72 (m, 4H), 1.52 (m, 2H), 1.35 (m, 2H).

Example 38 4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid 95 (preparation seeexample 36) and amine 14.

MS (ESI): 481.2 [M+H]⁺, 1H-NMR (CD₃OD): δ (ppm) 7.63 (s, 1H), 7.51 (s,1H), 7.23 (s, 1H), 7.13 (t, 1H), 7.04 (d, 1H), 6.6 (d, 1H), 6.57 (s,1H), 5.08 (s, 2H), 3.9 (m, 1H), 2.83-3.12 (m, 5H), 2.55 (m, 4H), 2.21(m, 2H), 2.11 (m, 1H), 1.84-2.0 (m, 3H), 1.51-1.83 (m, 5H), 0.99 (d,3H).

Example 39 4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid, 95 (see example 36)and amine 50.

MS (ESI): 481.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.47 (s, 1H), 8.14(d, 1H), 7.82 (s, 1H), 7.68 (s, 1H), 7.22 (s, 1H), 7.05 (t, 1H), 6.99(d, 1H), 6.62 (s, 1H), 6.60 (d, 1H), 5.03 (d, 2H), 4.45 (d, 1H), 3.73(m, 1H), 3.37 (m, 1H), 2.9 (m, 1H), 2.8 (m, 1H), 2.6-2.75 (m, 3H),2.05-2.37 (m, 5H), 1.9 (m, 1H), 1.65-1.8 (m, 4H), 1.42-1.62 (m, 2H),1.2-1.4 (m, 2H), 0.92 (d, 3H).

Example 40 4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid, 95 (see example 36)and amine 56.

MS (ESI): 495.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.46 (s, 1H), 8.14(d, 1H), 7.82 (s, 1H), 7.68 (s, 1H), 7.23 (s, 1H), 7.05 (t, 1H), 6.99(d, 1H), 6.62 (s, 1H), 6.6 (d, 1H), 5.03 (s, 2H), 4.43 (d, 1H), 3.72 (m,1H), 2.58-2.94 (m, 5H), 2.32 (m, 1H), 2.24 (m, 1H), 2.03-2.19 (m, 2H),1.84-1.96 (m, 2H), 1.66-1.79 (m, 3H), 1.42-1.62 (m, 2H), 1.2-1.41 (m,3H), 0.91 (d, 3H), 0.86 (d, 3H).

Example 41 4-Benzyloxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized analogously to Example 1 from4-Benzyloxy-1H-indole-2-carboxylic acid and amine 5.

MS (ESI): 475.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.5 (s, 1H), 8.16 (d,1H), 7.3-7.54 (m, 5H), 7.26 (d, 1H), 7.06 (t, 1H), 7.0 (d, 1H), 6.6 (d,1H), 5.18 (s, 2H), 3.74 (m, 1H), 2.86 (m, 2H), 2.47-2.62 (m, 6H), 2.37(m, 2H), 2.0 (m, 2H), 1.75 (m, 2H), 1.45-1.64 (m, 10H).

Example 42 4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (97)(preparation see below) and amine 61 analogously to the method describedin example 1.

Yield: 200 mg (59%). MS (ESI): 575 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 10.1-10.7 (m, 2H), 8.5 (t, 1H), 8.24 (s, 1H), 7.75 (d,1H), 7.68 (d, 1H), 7.37 (dd, 1H), 7.25 (m, 1H), 7.1 (m, 1H), 7.05 (d,1H), 6.7 (d, 1H), 5.35 (s, 2H), 4.0 (m, 1H), 2.8-3.6 (m, 14H), 1.3-2.1(m, 12H).

Reaction Scheme 13:

Synthesis of 4-Hydroxy-indole-1,2-dicarboxylic acid 1-tert-butyl ester2-ethyl ester (102) (1) Step A: 4-Benzyloxy-indole-1,2-dicarboxylic acid1-tert-butyl ester 2-ethyl ester (103)

4-Benzyloxy-1H-indole-2-carboxylic acid ethyl ester (50 g, 169.3 mmol)is dissolved in 500 ml of ethyl acetate and DMAP (141 mg, 3.4 mmol) isadded. Then the mixture is cooled to 0° C. and BOC₂O (36.9 g, 169.3mmol), dissolved in 20 ml of ethyl acetate, is added dropwise. Aftercompletion of addition the reaction mixture is allowed to stir overnight at room temperature. The mixture is washed with 1M tartaric acidand brine. The organic layers are dried over sodium sulfate andevaporated

Yield: 72 g of a colorless oil, which is used in the next step withoutfurther purification.

MS (ESI): 396 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 7.51 (m, 1H), 7.47 (m,2H), 7.40 (m, 1H), 7.38 (m, 2H), 7.31 (m, 1H), 7.21 (s, 1H), 6.92 (d,1H), 5.26 (s, 2H), 4.28 (q, 2H), 1.56 (s, 9H), 1.31 (t, 3H).

(2) Step B: 4-Hydroxy-indole-1,2-dicarboxylic acid 1-tert-butyl ester2-ethyl ester (102)

103 (46.2 g, 116.8 mmol) is dissolved in ethanol (300 ml) and afteraddition of ammonium formiate (8.3 g, 128.5 mmol) and 10% Pd—C (5 g) themixture is stirred at room temperature for 1 h. Then the mixture isfiltered off. Evaporation under reduced pressure gave 6.89 g of a whitesolid, which is further purified by recrystallisation fromether/hexanes.

Yield: 27.75 g (78%). MS (ESI): 304 [M−H]⁻, 1H-NMR (DMSO-d₆): δ (ppm)10.1 (s, 1H), 7.38 (d, 1H), 7.25 (s, 1H), 7.23 (dd, 1H), 6.65 (d, 1H),4.3 (q, 2H), 1.55 (s, 9H), 1.3 (t, 3H).

Synthesis of 4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid (97) (1) Step A: 2-(Benzotriazol-1-ylmethoxy)-5-chloro-benzaldehyde(98)

5-Chloro-2-hydroxy-benzaldehyde (8.45 g, 54 mmol) is dissolved in DMF(100 ml) and after addition of 1-(chlormethyl)-1H-benzotriazole (9.96 g,59.4 mmol) and K₂CO₃ (9.7 g, 70.2 mmol) the mixture is stirred at 45° C.for 1 h (TLC control). Then the mixture is evaporated under high vacuum.The residue is diluted with ethyl acetate, washed with brine and driedover Na2SO4. Evaporation gave 3.9 g of a colorless solid. The product isused in the next step without further purification.

Yield: 17 g (100%) of a white solid. MS (ESI): 288 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 10.01 (s, 1H), 8.08 (d, 1H), 7.97 (d, 1H), 7.78 (dd,1H), 7.68 (d, 1H), 7.62 (dd, 1H), 7.55 (d, 1H), 7.43 (dd, 1H), 6.95 (s,2H).

(2) Step B: 1-(4-Chloro-2-oxiranyl-phenoxymethyl)-1H-benzotriazole (99)

98 (15.5 g, 54 mmol) is dissolved in 150 ml of DCM and 150 ml of 40%aqueous sodium hydroxide solution. After addition of trimethylsulfoniumiodide (14.3 g, 70.2 mmol) and tetrabutylammoniumiodide (1.4 g, 3.8mmol), the mixture is refluxed for 18 h. The reaction mixture is dilutedwith DCM, washed with water and the organic layers are dried overNa2SO4. Evaporation gave 18.7 g of a yellow oil, which is furtherpurified by flash-chromatography (silicagel, ethyl acetate/hexanes 3:7)

Yield: 11.7 g (72%) of a colorless oil. MS (ESI): 302 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 8.08 (d, 1H), 7.92 (d, 1H), 7.62 (dd, 1H), 7.5 (dd,1H), 7.45 (dd, 1H), 7.4 (dd, 1H), 6.92 (d, 1H), 6.83 (dd, 1H), 3.8 (m,1H), 2.8 (dd, 2H), 2.48 (dd, 1H).

(3) Step C: (5-Chloro-benzofuran-3-yl)-methanol (100)

99 (25.7 g, 85.1 mmol) is dissolved in 300 ml of tetrahydrofurane andcooled to −78° C. A 2M solution of LDA in THF (93.7 ml, 187.4 mmol) isadded dropwise within 45 min. The reaction mixture is allow to warmup toroom temperature within 17 h. Then the reaction mixture is quenched withsaturated aqueous ammonium chloride solution and evaporated underreduced pressure. The residue is diluted with ethyl acetate, washed withwater and brine and dried over sodium sulfate. Evaporation gave 17.2 gof an brown resin which is further purified by flash-chromatography(silicagel, ethyl acetate/hexanes 2:8).

Yield: 10.4 g mg of a white solid (67%). MS (ESI): 181 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 7.91 (d, 1H), 7.72 (d, 1H), 7.56 (d, 1H), 7.32 (dd,1H), 5.18 (t, 1H), 4.58 (d, 2H).

(4) Step D: 4-(5-Chloro-benzofuran-3-ylmethoxy)-indole-1,2-dicarboxylicacid 1-tert-butyl ester 2-ethyl ester (101)

100 (4 g, 21.9 mmol), 102 (6.7 g, 21.9 mmol), triphenylphosphine (17.3g, 65.8 mmol) and 40% diethyl azadicarboxylate solution (31.8 ml, 65.8mmol) are dissolved in THF and cooled to 0° C. Then a solution ofN-ethyldiisopropylamine (11.2 ml, 65.8 mmol) in THF is added dropwise.After the addition is completed, the mixture is stirred at roomtemperature for 2 h. Then the mixture is evaporated under reducedpressure. The residue is diluted with ethyl acetate, washed withsaturated NaHCO3-solution and dried over Na2SO4. The crude product ispurified by Flash-chromatography (ethyl acetate/hexanes (3:7),silicagel).

Yield: 7.7 g (75%) of a slightly colored oil. MS (ESI): 469 [M]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 8.27 (s, 1H), 7.79 (d, 1H), 7.63 (d, 1H), 7.53 (d,1H), 7.40 (d, 1H), 7.36 (dd, 1H), 7.21 (s, 1H), 7.04 (d, 1H), 5.42 (s,2H), 4.29 (q, 2H), 1.55 (s, 9H), 1.29 (t, 3H).

(5) Step E: 4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid (97)

101 (7.7 g, 16.3 mmol) is dissolved in 15 ml of a 1:1:1 mixture ofTHF/water/ethanol and after addition of KOH pellets (5.4 g, 81.9 mmol)the mixture is stirred for 2 h at 85° C. Then the organic phase isevaporated under reduced pressure. The residue is dissolved in ethylacetate, acidified with 2M HCl and filtered off. The crude product ispurified by crystalisation from ethyl acetate.

Yield: 4.4 g (79%) of white crystals. MS (ESI): 340 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 12.8 (s, 1H), 11.7 (s, 1H), 8.25 (s, 1H), 7.79 (d,1H), 7.62 (d, 1H), 7.35 (dd, 1H), 7.15 (dd, 1H), 7.0-7.05 (m, 2H), 6.71(d, 1H), 5.39 (s, 2H).

Example 43 4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized from4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (97, seeexample 42) and amine 5 analogously to the method described in example1.

Yield: 52 mg (16%). MS (ESI): 549 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)10.98 (br s, 1H), 8.12 (s, 1H), 7.68 (d, 1H), 7.53 (d, 1H), 7.0-7.2 (m,5H), 6.65 (d, 1H), 5.43 (s, 2H), 3.75 (m, 1H), 2.35-2.65 (m, 12H), 2.1(m, 2H), 1.8 (m, 2H), 1.5-1.6 (m, 8H).

Example 44 4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized from4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (97, seeexample 42) and amine 21 analogously to the method described in example1.

Yield: 50 mg (24%). MS (ESI): 551 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.45 (s, 1H), 8.22 (s, 1H), 8.12 (d, 1H), 7.78 (s, 1H), 7.67 (d, 1H),7.37 (d, 1H), 7.18 (s, 1H), 7.08 (dd, 1H), 7.02 (d, 1H), 6.67 (m, 1H),5.33 (s, 2H), 4.49 (b, 1H), 3.7 (m, 1H), 3.4 (m, 1H), 2.85 (m, 2H), 2.7(m, 2H), 2.5 (m, 2H), 2.35 (m, 2H), 1.95 (m, 4H), 1.25-1.8 (m, 8H).

Example 45 4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized from4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (97, seeexample 42) and amine 14 analogously to the method described in example1.

Yield: 85 mg (45%). MS (ESI): 565 [M+H]⁺, 1H-NMR (120° C., DMSO-d₆): δ(ppm) 11.29 (br s, 1H), 8.2 (d, 1H), 8.1 (s, 1H), 7.74 (s, 1H), 7.57 (d,1H), 7.34 (d, 1H), 7.22 (s, 1H), 7.09 (m, 1H), 6.72 (d, 1H), 5.39 (s,2H), 2.6-4.1 (m, 15H), 1.75-2.2 (m, 8H), 1.00 (d, 3H).

Example 46 4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (97, seeexample 42) and amine 50 analogously to the method described in example1.

Yield: 125 mg (71%). MS (ESI): 565 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 10.3-10.7 (br, 2H), 8.52 (d, 1H), 8.24 (s, 1H), 7.75 (d,1H), 7.68 (d, 1H), 7.35 (dd, 1H), 7.23 (s, 1H), 7.1 (dd, 1H), 7.03 (d,1H), 6.7 (d, 1H), 5.35 (s, 2H), 5.1 (br, 1H), 4.05 (m, 1H), 2.7-3.7 (m,12H), 1.7-2.1 (m, 8H), 1.35/1.3 (d, 3H) (rotamers).

Example 47 4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (97, seeexample 42) and amine 56 analogously to the method described in example1.

Yield: 123 mg (64%). MS (ESI): 579 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 10.4-10.6 (br, 2H), 8.52 (d, 1H), 8.26 (s, 1H), 7.77 (d,1H), 7.68 (d, 1H), 7.38 (dd, 1H), 7.23 (s, 1H), 7.12 (dd, 1H), 7.03 (d,1H), 6.7 (d, 1H), 5.35 (s, 2H), 5.1 (br, 1H), 4.05 (m, 1H), 2.8-3.9 (m,13H), 1.9-2.1 (m, 6H), 1.31 (d, 3H), 0.94 (d, 3H).

Example 48 4-(4-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(4-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (104)(preparation see below) and amine 61 analogously to the method describedin example 1.

Yield: 49 mg (22.5%). MS (ESI): 559.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 10.5 (br d, 1H), 10.2 (br d, 1H), 8.45 (m, 1H), 8.25 (s,1H), 7.5 (d, 1H), 7.38 (m, 1H), 7.25 (m, 1H), 7.1 (m, 2H), 7.03 (d, 1H),6.7 (d, 1H), 5.3 (s, 2H), 4.0 (m, 1H), 2.8-3.6 (m, 14H), 1.3-2.1 (m,12H).

Synthesis of 4-(4-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid (104)

This compound is synthesized from 2-fluoro-6-hydroxy-benzaldehydeanalogously to the method described for 97 (see example 42).

Yield: 220 mg (49%) of white crystals. MS (ESI): 324.3 [M−H]⁻.

Example 49 4-(4-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(4-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (104,see example 48) and amine 21 analogously to the method described inexample 1.

Yield: 100 mg (61%). MS (ESI): 535 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.45 (s, 1H), 10.5 (br, 1H), 10.35 (br, 1H), 8.48 (d, 1H), 8.23 (m,2H), 7.5 (d, 1H), 7.35 (m, 1H), 7.2 (s, 1H), 7.1 (m, 1H), 7.03 (d, 1H),6.7 (d, 1H), 5.3 (s, 2H), 5.05 (br, 1H), 4.05 (m, 1H), 2.9-3.75 (m,13H), 1.65-2.1 (m, 8H).

Example 50 4-(Benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (105)(preparation see below) and amine 61 analogously to the method describedin example 1.

Yield: 68 mg (34%). MS (ESI): 541 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.56 (s, 1H), 10.5 (br d, 1H), 10.2 (br d, 1H), 8.5 (t, 1H), 8.18 (s,1H), 7.72 (d, 1H), 7.6 (d, 1H), 7.25-7.35 (m, 3H), 7.12 (d, 1H), 7.03(d, 1H), 6.75 (d, 1H), 5.57 (s, 2H), 4.01 (m, 1H), 2.8-3.6 (m, 14H),1.3-2.1 (m, 12H).

Synthesis of 4-(benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid(105)

This compound is synthesized from 2-hydroxy-benzaldehyde analogously tothe method described for 97 (see example 42).

MS (ESI): 306 [M−H]⁻, 1H-NMR (DMSO-d₆): δ (ppm) 12.8 (br s, 1H), 11.7(s, 1H), 8.15 (s, 1H), 7.73 (d, 1H), 7.58 (d, 1H), 7.33 (dd, 1H), 7.29(dd, 1H), 7.15 (dd, 1H), 7.05 (s, 1H), 7.02 (d, 1H), 6.73 (d, 1H), 5.38(s, 2H).

Example 51 4-(Benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-(benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 105 (see example50) and amine 21.

MS (ESI): 517.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.48 (s, 1H), 8.17(s, 1H), 8.1 (d, 1H), 7.72 (d, 1H), 7.61 (d, 1H), 7.35 (t, 1H), 7.28 (d,1H), 7.18 (s, 1H), 7.09 (t, 1H), 7.01 (d, 1H), 6.71 (d, 1H), 5.35 (s,2H), 4.48 (d, 1H), 3.71 (m, 1H), 3.39 (m, 1H), 2.84 (m, 2H), 2.69 (m,2H), 2.35 (m, 4H) 1.98 (m, 4H), 1.69 (m, 4H), 1.48 (m, 2H), 1.34 (m,2H).

Example 52 4-(Benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-(benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (105, see example50) and amine 14.

MS (ESI): 531.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.48 (s, 1H), 8.17(s, 1H), 8.11 (d, 1H), 7.72 (d, 1H), 7.61 (d, 1H), 7.35 (t, 1H), 7.29(t, 1H), 7.19 (s, 1H), 7.09 (t, 1H), 7.01 (d, 1H), 6.71 (d, 1H), 5.35(d, 2H), 4.47 (d, 1H), 3.7 (m, 1H), 3.3 (m, 1H), 2.65-2.91 (m, 5H), 2.34(m, 4H), 1.83-2.04 (m, 3H), 1.65-1.77 (m, 3H), 1.27-1.63 (m, 5H), 0.85(d, 3H).

Example 53 4-(Benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-(benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 105 (see example50) and amine 50.

MS (ESI): 531.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.48 (s, 1H), 8.17(s, 1H), 8.11 (d, 1H), 7.72 (d, 1H), 7.61 (d, 1H), 7.35 (t, 1H), 7.29(t, 1H), 7.19 (d, 1H), 7.09 (t, 1H), 7.01 (d, 1H), 6.71 (d, 1H), 5.35(s, 2H), 4.44 (d, 1H), 3.7 (br m, 1H), 3.35 (m, 1H), 2.97 (m, 1H),2.6-2.9 (m, 4H), 2.0-2.35 (m, 4H), 1.89 (m, 1H), 1.63-1.77 (m, 3H),1.4-1.6 (m, 3H), 1.2-1.38 (m, 3H), 0.90 (d, 3H).

Example 54 4-(Benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-(benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 105 (see example50) and amine 56.

MS (ESI): 545.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.48 (s, 1H), 8.17(s, 1H), 8.11 (d, 1H), 7.72 (d, 1H), 7.61 (d, 1H), 7.35 (t, 1H), 7.29(t, 1H), 7.19 (s, 1H), 7.09 (t, 1H), 7.01 (d, 1H), 6.71 (d, 1H), 5.35(s, 2H), 4.43 (d, 1H), 3.71 (m, 1H), 2.59-2.92 (m, 6H), 2.31 (m, 1H),2.22 (m, 1H), 2.01-2.17 (m, 2H), 1.88 (m, 2H), 1.66-1.76 (m, 3H),1.2-1.58 (m, 4H), 0.89 (d, 3H), 0.86 (d, 3H).

Example 55 4-(6-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (106)(preparation see below) and amine 61 analogously to the method describedin example 1.

Yield: 80 mg (41.2%). MS (ESI): 559 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.55 (s, 1H), 10.63 (br d, 1H), 10.35 (br d, 1H), 8.5 (m, 1H), 8.2 (s,1H), 7.72 (dd, 1H), 7.58 (dd, 1H), 7.25 (m, 1H), 7.2 (m, 1H), 7.1 (d,1H), 7.03 (d, 1H), 6.7 (d, 1H), 5.35 (s, 2H), 4.0 (m, 1H), 2.6-3.6 (m,14H), 1.3-2.1 (m, 12H).

Reaction Scheme 14:

Synthesis of 4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid (106) (1) Step A: (3-Fluoro-phenoxy)-acetic acid ethyl ester (107)

3-Fluoro-phenol (100 g, 892 mmol) is dissolved in acetone (250 ml) andafter addition of chloro-acetic acid ethyl ester (114 ml, 1.07 mol) andK2CO3 (249 g, 1.78 mol) the mixture is refluxed for 24 h. After coolingdown to 0° C., the mixture is filtrated and the filtrate is evaporatedunder reduced pressure. Yield: 198 g (100%) of a red oil.

(2) Step B: 2-(3-Fluoro-phenoxy)-3-oxo-succinic acid diethyl ester (108)

60% NaH in mineral oil (19.5 g, 488.4 mmol) is covered with 600 ml ofdry diethyl ether. Ethanol (28.1 ml, 444 mmol) is added dropwise within25 min. Then oxalic acid diethyl ester (66 ml, 488 mmol) is addeddropwise within 20 min. After 10 min stirring at room temperature, themixture is heated to reflux. A solution of 107 (88 g, 444 mmol) in 80 mlof dry diethyl ether is added dropwise within 30 min and the mixture isallowed to reflux for 1 hour. After cooling down to room temperature,the reaction mixture is poured on 2M HCl (400 ml)/ice (400 g) andextracted with diethyl ether. The organic layers are dried over sodiumsulfate, filtrated and evaporated. The crude product is purified byfiltration over silica gel (ethyl acetate/hexane 1:1). Evaporation gave140 g of an red oil. The mineral oil could be removed using a separatoryfunnel. Yield: 132 g (100%).

(3) Step C: 6-Fluoro-benzofuran-2,3-dicarboxylic acid diethyl ester(109)

108 (66 g, 221.3 mmol) is dissolved in 245 ml of cooled (−15° C.) conc.sulfuric acid and stirred for 3 h whereas the reaction mixture slowlywarmed up to room temperature. Then the mixture is poured onto 1 kg ofice and extracted with diethyl ether. The organic layers are washed withbrine, dried over sodium sulfate, filtrated and evaporated. The crudeproduct is used in the next step without further purification.

Yield: 19.7 g (32%) of a yellow oil. MS (ESI): 281 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 7.88 (dd, 1H), 7.82 (dd, 1H), 7.35 (ddd, 1H), 4.38(m, 4H), 1.33 (t, 3H), 1.32 (t, 6H). The cyclisation gave exclusivelythe 6-substituted benzofurane.

(4) Step D: 6-Fluoro-benzofuran-3-carboxylic acid ethyl ester (110)

109 (40 g, 142.7 mmol) is dissolved in 300 ml of a DMSO and afteraddition of sodium chloride (16.7 g, 285.4 mmol) and water (5.1 ml) themixture is stirred for 4 h at 160° C. (temperature of reaction mixture).Then the mixture is allowed to cool down and evaporated at high vacuum.The residue is dissolved in ethyl acetate, washed with water and brineand dried over sodium sulfate. Evaporation gave 14.8 g of an red oil,which is further purified by filtration over silica gel (ethylacetate/hexanes 2:8).

Yield: 7.8 g (26%) of a yellow solid. MS (ESI): 208 [M]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 8.77 (s, 1H), 7.92 (dd, 1H), 7.68 (dd, 1H), 7.29(ddd, 1H), 4.35 (q, 2H), 1.32 (t, 3H).

(5) Step E: (6-Fluoro-benzofuran-3-yl)-methanol (111)

1M LiAlH4-solution in THF (75.9 ml, 75.9 mmol) is diluted with 100 ml ofTHF and cooled to 0° C. 110 (7.9 g, 37.9 mmol) is dissolved in 100 ml ofTHF and added dropwise within 30 min. After completed addition themixture is allowed to stir at rt for 2 h. Then the reaction mixture iscooled to −15° C. and 10 ml of a 1M NaOH solution is added very slowly.The mixture is filtrated over celite and evaporation under reducedpressure gave 5.3 g of a yellow oil.

(6) Step F: 4-(6-Fluoro-benzofuran-3-ylmethoxy)-indole-1,2-dicarboxylicacid 1-tert-butyl ester 2-ethyl ester (112)

111 (2 g, 12 mmol), 102 (3.7 g, 12 mmol), triphenylphosphine (9.4 g,36.1 mmol) and DIPEA (6.2 ml, 36.1 mmol) are dissolved in 50 ml of THFand cooled to 0° C. Then 40% ethyl azodicarboxylate solution in THF(15.7 ml, 36.1 mmol) is added dropwise. After completed addition themixture is stirred for 16 h (TLC control) at rt. Then the mixture isevaporated under reduced pressure. The residue is diluted with ethylacetate, washed sat. NaHCO3- and NaCl-solution, and dried over Na2SO4.The crude product is purified by Flash-chromatography (ethylacetate/hexanes (1:9), silicagel).

Yield: 1.2 g (22%) of a red oil. MS (ESI): 454 [M+H]⁺, 1H-NMR (DMSO-d₆):δ (ppm) 8.22 (s, 1H), 7.73 (dd, 1H), 7.58 (dd, 1H), 7.53 (d, 1H),7.38-7.40 (m, 2H), 7.15-7.7.25 (m, 1H), 7.05 (d, 1H), 5.43 (s, 2H), 4.05(q, 2H), 1.55 (s, 9H), 1.29 (t, 3H).

(7) Step G: 4-(6-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid (106)

112 (1.2 g, 2.6 mmol) is dissolved in 30 ml of a 1:1:1 mixture of THF,ethanol and water. And after addition of KOH pellets (742 mg, 13.2 mmol)the mixture is stirred for 2 h (TLC control) at 85° C. Then the organicsolvent are removed under reduced pressure. The residue is cooled to 0°C. and treated with 2M HCl. The crude product is filtered off and driedunder high vacuum. The crude product (800 mg) is recrystallized fromethyl acetate.

Yield: 520 mg (60%) of colorless crystals. MS (ESI): 324 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 12.8 (br s, 1H), 11.7 (s, 1H), 8.18 (s, 1H), 7.73(dd, 1H), 7.57 (dd, 1H), 7.18 (dd, 1H), 7.15 (d, 1H), 7.05 (s, 1H), 7.02(d, 1H), 6.72 (d, 1H), 5.38 (s, 2H).

Example 56 4-(6-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (106,see example 55) and amine 21 analogously to the method described inexample 1.

Yield: 70 mg (38%). MS (ESI): 535 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.5(s, 1H), 10.55 (br, 1H), 10.45 (br, 1H), 8.5 (br d, 1H), 8.2 (s, 1H),7.7 (dd, 1H), 7.6 (dd, 2H), 7.15-7.25 (m, 2H), 7.1 (dd, 1H), 7.03 (d,1H), 5.35 (s, 2H), 5.0 (br, 1H), 4.05 (m, 1H), 2.9-3.7 (m, 13H), 1.7-2.1(m, 8H).

Example 57 4-(6-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (106,see example 55) and amine 14 analogously to the method described inexample 1.

Yield: 135 mg (71%). MS (ESI): 549 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 10.65 (br, 2H), 8.52 (d, 1H), 8.2 (s, 1H), 7.72 (dd, 1H),7.58 (dd, 1H), 7.24 (s, 1H), 7.2 (m, 1H), 7.1 (dd, 1H), 7.04 (d, 1H),6.72 (d, 1H), 5.35 (s, 2H), 2.6-4.2 (m, 14H), 1.75-2.2 (m, 8H), 0.93 (d,3H).

Example 58 4-(6-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (106,see example 55) and amine 50 analogously to the method described inexample 1.

Yield: 75 mg (39%). MS (ESI): 549 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.55 (s, 1H), 10.3-10.7 (br, 2H), 8.53 (d, 1H), 8.2 (s, 1H), 7.72 (dd,1H), 7.58 (dd, 1H), 7.24 (s, 1H), 7.2 (m, 1H), 7.1 (dd, 1H), 7.03 (d,1H), 6.71 (d, 1H), 5.33 (s, 2H), 5.1 (br, 1H), 2.8-4.1 (m, 13H), 1.7-2.2(m, 8H), 1.35/1.3 (d, 3H) (rotamers).

Example 59 4-(6-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 106(see example 55) and amine 56.

MS (ESI): 463.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.48 (s, 1H), 8.19(s, 1H), 8.11 (d, 1H), 7.71 (dd, 1H), 7.58 (dd, 1H), 7.19 (m, 2H), 7.09(t, 1H), 7.01 (d, 1H), 6.7 (d, 1H), 5.34 (s, 2H), 4.43 (d, 1H), 3.71 (m,1H), 2.58-2.92 (m, 6H), 2.31 (m, 1H), 2.22 (m, 1H), 2.02-2.18 (m, 2H),1.89 (m, 2H), 1.64-1.78 (m, 3H), 1.42-1.59 (m, 2H), 1.2-1.4 (m, 2H), 0.9(d, 3H), 0.86 (d, 3H).

Example 60 4-(5-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide

This compound is synthesized from4-(5-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (113)(preparation see below) and amine 61 analogously to the method describedin example 1.

Yield: 840 mg (72.5%). MS (ESI): 559 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.45 (s, 1H), 8.23 (s, 1H), 8.1 (d, 1H), 7.64 (dd, 1H), 7.48 (dd, 1H),7.17 (m, 2H), 7.08 (dd, 1H), 7.0 (d, 1H), 6.68 (d, 1H), 5.35 (s, 2H),3.75 (m, 1H), 2.65-2.85 (m, 4H), 2.47 (m, 1H), 2.25 (dd, 1H), 1.2-2.05(m, 20H).

Synthesis of 4-(5-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid (113)

This compound is synthesized from 4-fluoro-phenol analogously to themethod described for 106 (see example 55).

MS (ESI): 324.2 [M-1-1]⁻, 1H-NMR (DMSO-d₆): δ (ppm) 12.81 (br s, 1H),11.7 (s, 1H), 8.24 (s, 1H), 7.64 (dd, 1H), 7.51 (dd, 1H), 7.15 (m, 2H),7.05 (m, 2H), 6.7 (d, 1H), 5.37 (s, 2H).

Example 61 4-(5-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(5-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (113,see example 60) and amine 21 analogously to the method described inexample 1.

Yield: 160 mg (57%). MS (ESI): 535 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 10.65 (br, 1H), 10.55 (br, 1H), 8.51 (br d, 1H), 8.25 (s,1H), 7.65 (m, 1H), 7.45 (dd, 2H), 7.2 (s, 1H), 7.05-7.15 (m, 3H), 6.7(d, 1H), 5.35 (s, 2H), 4.12 (m, 1H), 3.84 (m, 1H), 2.9-3.7 (m, 13H),1.75-2.2 (m, 8H).

Example 62 4-(5-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[2-((3R,4R,5S)-4-hydroxy-3,5-dimethyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(5-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (113,see example 60) and amine 41 analogously to the method described inexample 1.

Yield: 110 mg (56%). MS (ESI): 563 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 10.5-10.7 (br, 2H), 8.5 (d, 1H), 8.22 (s, 1H), 7.63 (dd,1H), 7.49 (dd, 1H), 7.2 (m, 2H), 7.1 (d, 1H), 7.02 (d, 1H), 6.7 (d, 1H),5.32 (s, 2H), 5.05 (br, 1H), 4.05 (m, 1H), 2.6-3.8 (m, 13H), 1.8-2.1 (m,6H), 0.93 (d, 6H).

Example 63 4-(5-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(5-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (113,see example 60) and amine 50 analogously to the method described inexample 1.

Yield: 85 mg (45%). MS (ESI): 549 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.55 (s, 1H), 10.2-10.6 (br, 2H), 8.5 (d, 1H), 8.24 (s, 1H), 7.65 (dd,1H), 7.5 (m, 1H), 7.15-7.3 (m, 2H), 7.1 (dd, 1H), 7.03 (d, 1H), 6.71 (d,1H), 5.33 (s, 2H), 5.04 (br, 1H), 2.8-4.1 (m, 13H), 1.7-2.2 (m, 8H),1.35/1.3 (d, 3H) (rotamers).

Example 64 4-(5-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-(5-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 113(see example 60) and amine 56.

MS (ESI): 563.1 [M+H]⁺, 1H-NMR (CD₃OD): δ (ppm) 7.95 (s, 1H), 7.48 (dd,1H), 7.43 (dd, 1H), 7.21 (s, 1H), 7.15 (t, 1H), 7.02-7.12 (m, 2H), 6.69(d, 1H), 5.34 (s, 2H), 3.86 (m, 1H), 2.72-3.12 (m, 6H), 2.51 (m, 1H),2.17-2.41 (m, 3H), 1.97-2.15 (m, 2H), 1.81-1.96 (m, 3H), 1.45-1.76 (m,4H), 1.05 (d, 3H), 0.98 (d, 3H).

Example 65 4-(7-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(7-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (114)(preparation see below) and amine 61 analogously to the method describedin example 1.

Yield: 194 mg (40%). MS (ESI): 559 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 10.2-10.7 (br, 2H), 8.45 (dd, 1H), 8.28 (s, 1H), 7.58 (dd,1H), 7.2-7.3 (m, 3H), 7.1 (m, 1H), 7.05 (d, 1H), 6.72 (d, 1H), 5.38 (s,2H), 4.0 (m, 1H), 2.65-2.85 (m, 6H), 1.2-2.05 (m, 20H).

Synthesis of 4-(7-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid (114)

This compound is synthesized from 2-fluoro-phenol analogously to themethod described for 106 (see example 55).

MS (ESI): 324.2 [M-1-1]⁻, 1H-NMR (DMSO-d₆): δ (ppm) 12.85 (br s, 1H),11.75 (s, 1H), 8.25 (s, 1H), 7.58 (dd, 1H), 7.2-7.3 (m, 2H), 7.15 (dd,1H), 7.05 (s, 1H), 7.02 (d, 1H), 6.72 (d, 1H), 5.4 (s, 2H).

Example 664-(4,6-Difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(4,6-difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid(115) (preparation see below) and amine 61 analogously to the methoddescribed in example 1.

Yield: 155 mg (82%). MS (ESI): 577 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 10.5 (br d, 1H), 10.2 (br d, 1H), 8.45 (br d, 1H), 8.25(s, 1H), 7.55 (d, 1H), 7.2-7.25 (m, 2H), 7.1 (m, 1H), 7.05 (d, 1H), 6.7(d, 1H), 5.3 (s, 2H), 4.0 (m, 1H), 2.8-3.6 (m, 14H), 1.3-2.1 (m, 12H).

Synthesis of4-(4,6-Difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid(115)

This compound is synthesized from 3,5-difluoro-phenol analogously to themethod described for 106 (see example 55).

MS (ESI): 342 [M−H]⁻, 1H-NMR (DMSO-d₆): δ (ppm) 12.8 (br s, 1H), 11.6(s, 1H), 8.24 (s, 1H), 7.51 (dd, 1H), 7.2 (ddd, 1H), 7.15 (dd, 1H), 7.04(d, 1H), 7.02 (s, 1H), 6.7 (d, 1H), 5.32 (s, 2H).

Example 674-(4,6-Difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(4,6-difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid(115, see example 66)) and amine 21 analogously to the method describedin example 1.

Yield: 90 mg (49%). MS (ESI): 553 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.5(s, 1H), 10.5 (br, 1H), 10.35 (br, 1H), 8.48 (br d, 1H), 8.25 (s, 1H),7.54 (d, 1H), 7.2 (m, 2H), 7.12 (dd, 1H), 7.03 (d, 1H), 6.7 (d, 1H), 5.3(s, 2H), 5.05 (br, 1H), 4.07 (m, 1H), 2.9-3.75 (m, 13H), 1.65-2.1 (m,8H).

Example 684-(4,6-Difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(4,6-difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid(115, see example 66) and amine 14 analogously to the method describedin example 1.

Yield: 125 mg (67%). MS (ESI): 567 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 10.65 (br, 2H), 8.5 (d, 1H), 8.25 (s, 1H), 7.53 (dd, 1H),7.2-7.3 (m, 2H), 7.1 (dd, 1H), 7.02 (d, 1H), 6.7 (d, 1H), 5.3 (s, 2H),2.6-4.1 (m, 14H), 1.75-2.2 (m, 8H), 0.93 (d, 3H).

Example 694-(4,6-Difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(4,6-difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid(115, see example 66) and amine 50 analogously to the method describedin example 1.

Yield: 105 mg (56%). MS (ESI): 567 [M+H]⁺, 1H-NMR (120° C., DMSO-d₆): δ(ppm) 11.5 (s, 1H), 10.3-10.7 (br, 2H), 8.52 (d, 1H), 8.26 (s, 1H), 7.53(d, 1H), 7.2 (m, 2H), 7.1 (dd, 1H), 7.02 (d, 1H), 6.7 (d, 1H), 5.3 (s,2H), 5.05 (br, 1H), 4.05 (m, 1H), 2.9-3.9 (m, 12H), 1.7-2.2 (m, 8H),1.34 (d, 3H).

Example 704-(4,6-Difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(4,6-difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid(115, see example 66) and amine 56 analogously to the method describedin example 1.

Yield: 130 mg (68%). MS (ESI): 581 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 10.4-10.6 (br, 2H), 8.5 (d, 1H), 8.27 (s, 1H), 7.55 (d,1H), 7.2 (m, 2H), 7.1 (dd, 1H), 7.03 (d, 1H), 6.7 (d, 1H), 5.3 (s, 2H),5.1 (br, 1H), 4.05 (m, 1H), 2.8-3.9 (m, 13H), 1.9-2.1 (m, 6H), 1.3 (d,3H), 0.93 (d, 3H).

Example 71 4-(7-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(7-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (116)(preparation see below) and amine 61 analogously to the method describedin example 1.

Yield: 55 mg (29%). MS (ESI): 575 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.5(s, 1H), 10.1-10.6 (br, 2H), 8.5 (dd, 1H), 8.3 (s, 1H), 7.7 (d, 1H),7.48 (d, 1H), 7.32 (dd, 1H), 7.25 (m, 1H), 7.1 (m, 1H), 7.05 (d, 1H),6.7 (d, 1H), 5.38 (s, 2H), 4.0 (m, 1H), 2.65-2.85 (m, 6H), 1.2-2.05 (m,20H).

Synthesis of 4-(7-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid (116)

This compound is synthesized from 2-chloro-phenol analogously to themethod described for 106 (see example 55).

MS (ESI): 340 [M−H]⁻, 1H-NMR (DMSO-d₆): δ (ppm) 10.86 (s, 1H), 8.25 (s,1H), 7.71 (d, 1H), 7.42 (d, 1H), 7.30 (dd, 1H), 6.93 (m, 2H), 6.58 (d,1H), 6.34 (s, 1H), 5.36 (s, 2H) (potassium salt).

Example 72 4-(6-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(6-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (117)(preparation see below) and amine 61 analogously to the method describedin example 1.

Yield: 85 mg (49.8%). MS (ESI): 575 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 10.6 (br d, 1H), 10.3 (br d, 1H), 8.49 (br dd, 1H), 8.22(s, 1H), 7.8 (d, 1H), 7.72 (d, 1H), 7.38 (dd, 1H), 7.25 (m, 1H), 7.1 (m,1H), 7.03 (d, 1H), 6.7 (d, 1H), 5.35 (s, 2H), 4.0 (m, 1H), 2.8-3.8 (m,14H), 1.3-2.1 (m, 12H).

Synthesis of 4-(6-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid (117)

This compound is synthesized from 3-chloro-phenol analogously to themethod described for 106 (see example 55). The cyclisation withconcentrated sulphuric acid (Step C) gave a 1:1 mixture of the 4- and6-substituted benzofuranes, which could be separated in step D. MS(ESI): 340 [M−H].

Example 73 4-(6-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized from4-(6-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (117,see example 72) and amine 21 analogously to the method described inexample 1.

Yield: 63 mg (34%). MS (ESI): 551 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.5(s, 1H), 8.22 (s, 1H), 8.15 (br d, 1H), 7.81 (s, 1H), 7.75 (d, 1H), 7.35(dd, 1H), 7.18 (s, 1H), 7.1 (dd, 1H), 7.02 (d, 1H), 6.7 (d, 1H), 5.35(s, 2H), 4.75 (b, 1H), 2.1-3.9 (m, 14H), 1.4-1.8 (m, 8H).

Example 74 4-(6-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized from4-(6-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (117,see example 72) and amine 14 analogously to the method described inexample 1.

Yield: 55 mg (32%). MS (ESI): 565 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.55 (s, 1H), 10.5 (br, 2H), 8.48 (d, 1H), 8.22 (s, 1H), 7.80 (s, 1H),7.70 (d, 1H), 7.37 (d, 1H), 7.22 (s, 1H), 7.1 (dd, 1H), 7.02 (d, 1H),6.71 (d, 1H), 5.34 (s, 2H), 2.6-4.2 (m, 14H), 1.75-2.2 (m, 8H), 0.93 (d,3H).

Example 75 4-(6-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(6-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (117,see example 72) and amine 50 analogously to the method described inexample 1.

Yield: 85 mg (46%). MS (ESI): 565 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.5(s, 1H), 10.2-10.6 (br, 2H), 8.5 (d, 1H), 8.21 (s, 1H), 7.8 (d, 1H), 7.7(d, 1H), 7.35 (dd, 1H), 7.24 (s, 1H), 7.1 (dd, 1H), 7.03 (d, 1H), 6.7(d, 1H), 5.35 (s, 2H), 5.0 (br, 1H), 2.85-4.2 (m, 13H), 1.7-2.2 (m, 8H),1.35/1.3 (d, 3H) (rotamers).

Example 76 4-(4-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(4-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (118)(preparation see below) and amine 61 analogously to the method describedin example 1.

Yield: 230 mg (58.8%). MS (ESI): 575 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 10.6 (br d, 1H), 10.3 (br d, 1H), 8.45 (br dd, 1H), 8.3(s, 1H), 7.65 (dd, 1H), 7.3-7.4 (m, 2H), 7.25 (m, 1H), 7.1 (m, 1H), 7.03(d, 1H), 6.7 (d, 1H), 5.35 (s, 2H), 4.0 (m, 1H), 2.8-3.8 (m, 14H),1.3-2.1 (m, 12H).

Synthesis of 4-(4-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid (118)

This compound is synthesized from 3-chloro-phenol analogously to themethod described for 106 (see example 55). The cyclisation withconcentrated sulphuric acid (Step C) gave a 1:1 mixture of the 4- and6-substituted benzofuranes, which could be separated in step D. MS(ESI): 340 [M−H]⁻, 1H-NMR (DMSO-d₆): δ (ppm) 12.75 (br s, 1H), 11.7 (s,1H), 8.31 (s, 1H), 7.6 (dd, 1H), 7.35 (m, 2H), 7.15 (dd, 1H), 7.02 (m,2H), 6.75 (d, 1H), 5.42 (s, 2H).

Example 77 4-(4-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(4-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (118,see example 76) and amine 21 analogously to the method described inexample 1.

Yield: 160 mg (99%). MS (ESI): 551 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.52 (s, 1H), 10.35 (br, 1H), 10.2 (br, 1H), 8.5 (br, 1H), 8.31 (s,1H), 7.63 (d, 1H), 7.36 (m, 2H), 7.22 (s, 1H), 7.11 (dd, 1H), 7.03 (d,1H), 6.71 (d, 1H), 5.37 (s, 2H), 5.02 (br, 1H), 4.05 (m, 1H), 2.9-3.75(m, 13H), 1.65-2.1 (m, 8H).

Example 78 4-(4-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[2-((3R,4R,5S)-4-hydroxy-3,5-dimethyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(4-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (118,see example 76) and amine 41 analogously to the method described inexample 1.

Yield: 45 mg (39%). MS (ESI): 577 [M−H]⁻, 1H-NMR (DMSO-d₆): δ (ppm) 11.5(s, 1H), 10.45-10.7 (br, 2H), 8.47 (d, 1H), 8.32 (s, 1H), 7.65 (d, 1H),7.35 (m, 2H), 7.21 (s, 1H), 7.1 (dd, 1H), 7.02 (d, 1H), 6.71 (d, 1H),5.35 (s, 2H), 5.0 (br, 1H), 4.05 (m, 1H), 2.6-3.8 (m, 13H), 1.8-2.1 (m,6H), 0.93 (d, 6H).

Example 79 4-(4-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized from4-(4-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (118,see example 76) and amine 50 analogously to the method described inexample 1.

Yield: 20 mg (13%). MS (ESI): 565 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.5(s, 1H), 8.3 (s, 1H), 8.1 (d, 1H), 7.62 (d, 1H), 7.35 (m, 2H), 7.2 (s,1H), 7.1 (dd, 1H), 7.0 (d, 1H), 6.7 (d, 1H), 5.4 (s, 2H), 4.5 (br, 1H),4.05 (m, 1H), 3.7 (m, 1H), 2.6-2.9 (m, 4H), 1.1-2.4 (m, 15H), 0.9 (d,3H).

Example 80 4-(7-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(7-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (119)(preparation see below) and amine 61 analogously to the method describedin example 1.

Yield: 130 mg (68.1%). MS (ESI): 571 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.55 (s, 1H), 10.5 (br d, 1H), 10.2 (br d, 1H), 8.47 (dd, 1H), 8.13 (s,1H), 7.25 (m, 2H), 7.2 (dd, 1H), 7.09 (d, 1H), 7.02 (d, 1H), 6.95 (d,1H), 6.72 (d, 1H), 5.32 (s, 2H), 4.0 (m, 1H), 3.83 (s, 3H), 2.8-3.8 (m,14H), 1.3-2.1 (m, 12H).

Synthesis of 4-(7-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid (119)

This compound is synthesized from 2-methoxy-phenol analogously to themethod described for 106 (see example 55).

MS (ESI): 336 [M−H]⁻, 1H-NMR (DMSO-d₆): δ (ppm) 12.8 (br s, 1H), 11.54(br s, 1H), 8.11 (s, 1H), 7.28 (d, 1H), 7.18 (dd, 1H), 7.09 (m, 1H), 7.0(d, 1H), 6.95 (d, 1H), 6.92 m, 1H), 6.70 (d, 1H), 5.35 (s, 2H), 3.92 (s,3H).

Example 81 4-(7-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid [1-(2-piperidin-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized from4-(7-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (119,see example 80) and amine 1 analogously to the method described inexample 1.

Yield: 162 mg (48%). MS (ESI): 531 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.53 (s, 1H), 10.55 (br, 1H), 10.31 (br, 1H), 8.49 (d, 1H), 8.12 (s,1H), 7.25 (dd, 1H), 7.22 (br s, 1H), 7.19 (dd, 1H), 7.1 (dd, 1H), 7.02(d, 1H), 7.95 (d, 1H), 6.7 (d, 1H), 5.31 (s, 2H), 4.05 (m, 1H), 3.93 (s,3H), 3.5-3.8 (m, 8H), 3.1 (m, 2H), 2.9 (m, 2H), 1.7-2.1 (m, 8H), 1.4 (m,2H).

Example 82 4-(7-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(7-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (119,see example 80) and amine 21 analogously to the method described inexample 1.

Yield: 135 mg (73%). MS (ESI): 547 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.45 (s, 1H), 10.5 (br, 1H), 10.4 (br, 1H), 8.5 (br, 1H), 8.14 (s, 1H),7.2-7.3 (m, 3H), 7.1 (dd, 1H), 7.0 (d, 1H), 6.95 (d, 1H), 6.7 (d, 1H),5.32 (s, 2H), 5.05 (br, 1H), 4.05 (m, 1H), 3.93 (s, 3H), 2.7-3.7 (m,13H), 1.6-2.1 (m, 8H).

Example 83 4-(7-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(7-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (119,see example 80) and amine 14 analogously to the method described inexample 1.

Yield: 100 mg (53%). MS (ESI): 561 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 10.6 (br, 2H), 8.5 (d, 1H), 8.13 (s, 1H), 7.18-7.3 (m,3H), 7.1 (dd, 1H), 7.03 (d, 1H), 6.96 (d, 1H), 6.71 (d, 1H), 5.33 (s,2H), 3.95 (s, 3H), 2.6-4.2 (m, 14H), 1.75-2.2 (m, 8H), 0.93 (d, 3H).

Example 84 4-(7-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(7-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (119,see example 80) and amine 50 analogously to the method described inexample 1.

Yield: 166 mg (94%). MS (ESI): 561 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 10.2-10.6 (br, 2H), 8.5 (d, 1H), 8.14 (s, 1H), 7.28 (d,1H), 7.23 (s, 1H), 7.2 (dd, 1H), 7.1 (dd, 1H), 7.03 (d, 1H), 6.95 (d,1H), 6.7 (d, 1H), 5.33 (s, 2H), 5.05 (br, 1H), 3.93 (s, 3H), 2.9-4.1 (m,13H), 1.7-2.2 (m, 8H), 1.35/1.3 (d, 3H) (rotamers).

Example 85 4-(7-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-(7-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 119(see example 80) and amine 56.

MS (ESI): 575.1 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.49 (s, 1H), 8.15(s, 1H), 8.13 (d, 1H), 7.26 (d, 1H), 7.22 (t, 1H), 7.2 (s, 1H), 7.1 (t,1H), 7.02 (d, 1H), 6.97 (d, 1H), 6.71 (d, 1H), 5.34 (s, 2H), 4.43 (d,1H), 3.95 (s, 3H), 3.72 (m, 1H), 2.6-2.93 (m, 6H), 2.31 (m, 1H), 2.23(m, 1H), 2.03-2.17 (m, 2H), 1.89 (m, 2H), 1.66-1.77 (m, 3H), 1.42-1.58(m, 2H), 1.2-1.4 (m, 2H), 0.89 (d, 3H), 0.85 (d, 3H).

Example 86 4-(6-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide

This compound is synthesized from4-(6-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (120)(preparation see below) and amine 61 analogously to the method describedin example 1.

Yield: 108 mg (63.8%). MS (ESI): 571 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.45 (s, 1H), 8.1 (d, 1H), 8.03 (s, 1H), 7.55 (d, 1H), 7.2 (m, 2H),7.08 (dd, 1H), 7.0 (d, 1H), 6.93 (dd, 1H), 6.7 (d, 1H), 5.3 (s, 2H),3.78 (s, 3H), 3.73 (m, 1H), 2.65-2.85 (m, 4H), 2.47 (m, 1H), 2.25 (dd,1H), 1.2-2.05 (m, 20H).

Synthesis of 4-(6-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid (120)

This compound is synthesized from 3-methoxy-phenol analogously to themethod described for 106 (see example 55). The cyclisation withconcentrated sulphuric acid (Step C) gave exclusively the 6-substitutedbenzofurane.

MS (ESI): 336 [M−H]⁻, 1H-NMR (DMSO-d₆): δ (ppm) 12.81 (br s, 1H), 11.71(s, 1H), 8.02 (s, 1H), 7.56 (d, 1H), 7.18 (s, 1H), 7.13 (dd, 1H), 7.01(s, 1H), 6.99 (m, 1H), 6.9 (dd, 1H), 6.71 (d, 1H), 5.33 (s, 2H), 3.78(s, 3H).

Example 87 4-(6-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized from4-(6-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (120,see example 86) and amine 5 analogously to the method described inexample 1.

Yield: 121 mg (50%). MS (ESI): 545 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 8.12 (d, 1H), 8.05 (s, 1H), 7.55 (d, 1H), 7.2 (m, 2H),7.08 (dd, 1H), 7.0 (d, 1H), 6.91 (dd, 1H), 6.7 (d, 1H), 5.3 (s, 2H), 3.8(s, 3H), 3.7 (m, 1H), 2.85 (m, 2H), 2.5-2.6 (m, 8H), 2.35 (dd, 2H), 2.0(m, 2H), 1.72 (m, 2H), 1.45-1.6 (m, 8H).

Example 88 4-(6-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized from4-(6-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (120,see example 86) and amine 21 analogously to the method described inexample 1.

Yield: 65 mg (27%). MS (ESI): 547 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.45 (s, 1H), 8.1 (br d, 1H), 8.03 (s, 1H), 7.55 (d, 1H), 7.18 (m, 2H),7.08 (dd, 1H), 7.0 (d, 1H), 6.9 (dd, 1H), 6.68 (d, 1H), 5.3 (s, 2H), 4.5(br, 1H), 3.78 (s, 3H), 3.72 (m, 1H), 3.4 (m, 1H), 2.9 (m, 2H), 2.7 (m,2H), 2.4 (m, 4H), 2.0 (m, 4H), 1.7 (m, 4H), 1.5 (m, 2H), 1.35 (m, 2H).

Example 89 4-(6-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(6-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (120,see example 86) and amine 14 analogously to the method described inexample 1.

Yield: 188 mg (89%). MS (ESI): 561 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.55 (s, 1H), 10.6 (br, 2H), 8.5 (d, 1H), 8.04 (s, 1H), 7.55 (d, 1H),7.1-7.3 (m, 3H), 7.0 (d, 1H), 6.9 (dd, 1H), 6.71 (d, 1H), 5.34 (s, 2H),2.6-4.2 (m, 14H), 1.75-2.2 (m, 8H), 0.93 (d, 3H).

Example 90 4-(6-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized from4-(6-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (120,see example 86) and amine 50 analogously to the method described inexample 1.

Yield: 63 mg (38%). MS (ESI): 561 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.5(s, 1H), 8.18 (d, 1H), 8.04 (s, 1H), 7.55 (d, 1H), 7.2 (m, 2H), 7.08(dd, 1H), 7.0 (d, 1H), 6.9 (dd, 1H), 6.7 (d, 1H), 5.3 (s, 2H), 4.75 (br,1H), 2.6-4.1 (m, 7H), 0.9-2.4 (m, 20H).

Example 91 4-(6-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-(6-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 120(see example 86) and amine 56.

MS (ESI): 575.1 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.47 (s, 1H), 8.03(s, 1H), 7.56 (d, 1H), 7.21 (d, 1H), 7.19 (s, 1H), 7.08 (t, 1H), 7.01(d, 1H), 6.92 (d, 1H), 6.69 (d, 1H), 5.3 (s, 2H), 3.8 (s, 3H), 3.65-3.8(m, 1H), 3.31 (m, 2H), 2.59-2.92 (m, 6H), 2.01-2.4 (m, 4H), 1.89 (m,2H), 1.65-1.78 (m, 3H), 1.19-1.59 (m, 4H), 0.89 (d, 3H), 0.86 (d, 3H).

Example 92 4-(5-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid [1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized from4-(5-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (121)(preparation see below) and amine 5 analogously to the method describedin example 1.

Yield: 77 mg (48%). MS (ESI): 545 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.48 (s, 1H), 8.13 (m, 2H), 7.48 (d, 1H), 7.23 (s, 1H), 7.2 (d, 1H),7.08 (dd, 1H), 7.02 (d, 1H), 6.92 (dd, 1H), 6.71 (d, 1H), 5.32 (s, 2H),3.74 (s, 3H), 3.68 (m, 1H), 2.83 (m, 2H), 2.5-2.6 (m, 8H), 2.35 (dd,2H), 1.98 (dd, 2H), 1.70 (m, 2H), 1.45-1.6 (m, 8H).

Synthesis of 4-(5-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid (121)

This compound is synthesized from 4-methoxy-phenol analogously to themethod described for 106 (see example 55).

460 mg (86%). MS (ESI): 336 [M−H]⁻, 1H-NMR (DMSO-d₆): δ (ppm) 12.79 (brs, 1H), 11.73 (s, 1H), 8.1 (s, 1H), 7.46 (d, 1H), 7.22 (d, 1H), 7.15(dd, 1H), 7.06 (d, 1H), 7.02 (d, 1H), 6.91 (dd, 1H), 6.73 (d, 1H), 5.37(s, 2H), 3.75 (s, 3H).

Example 93 4-(5-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized from4-(5-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (121,see example 92) and amine 21 analogously to the method described inexample 1.

Yield: 105 mg (65%). MS (ESI): 547 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 8.15 (d, 1H), 8.11 (s, 1H), 7.49 (d, 1H), 7.24 (s, 1H),7.20 (d, 1H), 7.09 (dd, 1H), 7.02 (d, 1H), 6.93 (dd, 1H), 6.71 (d, 1H),5.33 (s, 2H), 4.51 (br, 1H), 3.75 (s, 3H), 3.7 (m, 1H), 3.41 (m, 1H),2.85 (m, 2H), 2.7 (m, 2H), 2.39 (m, 4H), 2.0 (m, 4H), 1.71 (m, 4H), 1.52(m, 2H), 1.35 (m, 2H).

Example 94 4-(4-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-(4-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (122)(preparation see below) and1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-ylamine,61.

MS (ESI): 571.2 [M+H]⁺, 1H-NMR (CD₃OD): δ (ppm) 7.75 (s, 1H), 7.27 (s,1H), 7.25 (t, 1H), 7.18 (t, 1H), 7.10 (d, 1H), 7.07 (d, 1H), 6.75 (d,1H), 6.67 (d, 1H), 5.43 (s, 2H), 4.15 (br s, 1H), 3.4-3.8 (br m, 7H),3.83 (s, 3H), 2.9-3.25 (m, 4H), 2.53 (br m, 1H), 1.5-2.3 (m, 14H).

Synthesis of 4-(4-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid (122) (1) 4-Methoxy-benzofuran-3-carbaldehyde, 123

To a solution of 4-methoxy-3-methyl-benzofuran (J. Chem. Res. Synopses(1996),132) (4 g, 24.66 mmol) in 40 ml of dioxane is added seleniumdioxide (3.39 g, 29.59 mmol) and the mixture is heated under reflux for24 hours. It is then cooled and filtered. The solvent is evaporated andthe crude red solid is used as such in the next step.

Yield: 4.86 g (>100%). MS (ESI): 177.0 [M+H]⁺.

(2) (4-Methoxy-benzofuran-3-yl)-methanol, 124

The aldehyde 123 from above (4.34 g, 24.63 mmol) is dissolved in 10 mlof methanol and cooled in an ice-bath. Solid sodium borohydride (4.9 g,123.2 mmol) is added in portions and the mixture is stirred for 2 hours.It is then poured onto ice-cold HCl, extracted three times with DCM,dried and evaporated. The crude material is purified by chromatographyon silicagel using hexane and EtOAc (from 20% to 50%).

Yield: 1.82 g (41%). MS (ESI): 196.1 [M+NH₄]⁺.

(3) 4-(4-Methoxy-benzofuran-3-ylmethoxy)-indole-1,2-dicarboxylic acid1-tert-butyl ester 2-ethyl ester, 125

Indole ester 125 is prepared from alcohol 124 and 102 under Mitsunobuconditions (as described in example 50 for 105).

MS (ESI): 410.2 [(M−CMe₃)+H]⁺.

(4) 4-(4-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid,122

The title compound is prepared from ester 125 by cleavage withKOH/EtOH/THF (as described in example 50 for 105).

MS (ESI): 338.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.76 (s, 1H), 8.07(s, 1H), 7.29 (t, 1H), 7.21 (s, 1H), 7.19 (t, 1H), 7.1 (s, 1H), 7.04 (d,1H), 6.83 (d, 1H), 6.69 (d, 1H), 5.39 (s, 2H), 3.84 (s, 3H).

Example 95 4-(4-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid {1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-(4-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid 122(see example 94) and amine 21.

MS (ESI): 547.2 [M+H]⁺, 1H-NMR (CD₃OD): δ (ppm) 7.63 (s, 1H), 7.13 (s,1H), 7.12 (t, 1H), 7.04 (t, 1H), 6.98 (d, 1H), 6.94 (d, 1H), 6.62 (d,1H), 6.53 (d, 1H), 5.3 (s, 2H), 3.76 (m, 1H), 3.71 (s, 3H), 3.54 (m,1H), 2.85 (m, 2H), 2.73 (m, 2H), 2.42 (m, 4H), 2.07 (m, 4H), 1.81 (m,2H), 1.74 (m, 2H), 1.53 (m, 2H), 1.45 (m, 2H).

Example 96 4-(4-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-(4-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid 122(see example 94) and amine 14.

MS (ESI): 561.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.47 (s, 1H), 8.09(d, 1H), 8.01 (s, 1H), 7.27 (t, 1H), 7.23 (s, 1H), 7.2 (t, 1H), 7.09 (t,1H), 7.01 (d, 1H), 6.81 (d, 1H), 6.65 (d, 1H), 5.34 (s, 2H), 4.47 (d,1H), 3.79 (s, 3H), 3.7 (m, 1H), 2.64-2.93 (m, 4H), 2.35 (m, 4H),1.82-2.05 (m, 3H), 1.63-1.8 (m, 3H), 1.26-1.63 (m, 6H), 0.85 (d, 3H).

Example 97 4-(4-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid {1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-(4-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 122(see example 94) and amine 50.

MS (ESI): 561.2 [M+H]⁺, 1H-NMR (CD₃OD): δ (ppm) 7.62 (s, 1H), 7.13 (s,1H), 7.12 (t, 1H), 7.04 (t, 1H), 6.97 (d, 1H), 6.94 (d, 1H), 6.62 (d,1H), 6.52 (d, 1H), 5.3 (s, 2H), 3.74 (m, 1H), 3.71 (s, 3H), 3.46 (br m,1H), 2.93 (m, 1H), 2.77 (m, 1H), 2.65-2.75 (m, 3H), 2.4 (m, 1H), 2.28(m, 2H), 2.12 (m, 2H), 1.97 (m, 1H) 1.75 (m, 4H), 1.35-1.65 (m, 5H),0.93 (d, 3H).

Example 98 4-(4-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-(4-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 122(see example 94) and amine 56.

MS (ESI): 575.1 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.45 (s, 1H), 8.08(m, 1H), 8.0 (s, 1H), 7.27 (t, 1H), 7.22 (s, 1H), 7.2 (t, 1H), 7.09 (t,1H), 7.01 (d, 1H), 6.81 (d, 1H), 6.65 (d, 1H), 5.34 (s, 2H), 4.42 (m,1H), 3.79 (s, 3H), 3.73 (m, 1H), 2.58-2.92 (m, 6H), 2.31 (m, 1H), 2.22(m, 1H), 2.02-2.17 (m, 2H), 1.89 (m, 2H), 1.66-1.78 (m, 3H), 1.2-1.6 (m,4H), 0.9 (d, 3H), 0.86 (d, 3H).

Example 994-(4,6-dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(4,6-dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid 126(preparation see below) and amine 61 analogously to the method describedin example 1.

Yield: 146 mg (76.3%). MS (ESI): 601 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 10.1-10.7 (br, 2H), 8.1-8.5 (br, 1H), 7.89 (s, 1H), 7.3(br s, 1H), 7.1 (dd, 1H), 7.0 (d, 1H), 6.8 (s, 1H), 6.62 (d, 1H), 6.42(s, 1H), 5.28 (s, 2H), 4.0 (m, 1H), 3.8 (s, 3H), 3.75 (s, 3H), 2.8-3.8(m, 14H), 1.3-2.1 (m, 12H).

Synthesis of4-(4,6-dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid(126)

This compound is synthesized from 3,5-dimethoxyphenol analogously to themethod described for 106 (see example 55).

MS (ESI): 366 [M−H]⁻, 1H-NMR (DMSO-d₆): δ (ppm) 12.78 (br s, 1H), 11.7(s, 1H), 7.89 (s, 1H), 7.14 (dd, 1H), 7.08 (d, 1H), 7.02 (d, 1H), 6.78(d, 1H), 6.65 (d, 1H), 6.41 (d, 1H), 5.31 (s, 2H), 3.79 (s, 3H), 3.31(s, 3H).

Example 1004-(4,6-Dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-(4,6-dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid,126 (see example 99) and amine 21.

MS (ESI): 577.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.46 (s, 1H), 8.1 (d,1H), 7.87 (s, 1H), 7.22 (s, 1H), 7.08 (t, 1H), 7.0 (d, 1H), 6.81 (s,1H), 6.63 (d, 1H), 6.42 (s, 1H), 5.28 (s, 2H), 4.49 (m, 1H), 3.8 (s,3H), 3.76 (s, 3H), 3.73 (m, 1H), 3.16 (m, 1H), 2.85 (m, 2H), 2.69 (m,2H), 2.36 (m, 4H) 1.99 (m, 4H), 1.7 (m, 4H), 1.5 (m, 2H), 1.34 (m, 2H).

Example 1014-(4,6-Dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(4,6-dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid(126, see example 99) and amine 14 analogously to the method describedin example 1.

Yield: 85 mg (47%). MS (ESI): 591 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.5(s, 1H), 10.6 (br, 2H), 8.5 (d, 1H), 7.87 (s, 1H), 7.25 (s, 1H), 7.1(dd, 1H), 7.02 (d, 1H), 6.8 (d, 1H), 6.64 (d, 1H), 6.4 (d, 1H), 5.26 (s,2H), 5.1 (br, 1H), 4.05 (m, 1H), 3.8 (s, 3H), 3.77 (s, 3H), 2.6-3.8 (m,12H), 1.75-2.2 (m, 8H), 0.93 (d, 3H).

Example 1024-(4,6-Dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-(4,6-dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid,126 (see example 99) and amine 50.

MS (ESI): 591.3 [M+H]⁺, 1H-NMR (CD₃OD): δ (ppm) 7.63 (s, 1H), 7.23 (s,1H), 7.14 (t, 1H), 7.04 (d, 1H), 6.67 (s, 1H), 6.62 (d, 1H), 6.37 (s,1H), 5.35 (d, 2H), 3.85 (m, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.57 (m,1H), 3.05 (m, 1H), 2.89 (m, 1H), 2.75-2.87 (m, 3H), 2.35-2.55 (m, 3H),2.24 (m, 2H), 2.08 (m, 1H), 1.8-1.95 (m, 4H), 1.45-1.75 (m, 4H), 1.04(d, 3H).

Example 1034-(4,6-Dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-(4,6-dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid,126 (see example 99) and amine 56.

MS (ESI): 605.1 [M+H]⁺, 1H-NMR (CD₃OD): δ (ppm) 7.64 (s, 1H), 7.23 (s,1H), 7.15 (t, 1H), 7.05 (d, 1H), 6.69 (s, 1H), 6.64 (d, 1H), 6.38 (s,1H), 4.85 (s, 2H), 3.88 (m, 1H), 3.84 (s, 3H), 3.8 (s, 3H), 2.78-3.17(m, 6H), 2.57 (m, 1H), 2.23-2.47 (m, 3H), 2.03-2.21 (m, 2H), 1.87-1.98(m, 3H), 1.45-1.8 (m, 4H), 1.08 (d, 3H), 0.99 (d, 3H).

Example 1044-(5,6-dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(5,6-dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid 127(preparation see below) and amine 61 analogously to the method describedin example 1.

Yield: 146 mg (76.3%). MS (ESI): 569 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.45 (s, 1H), 10.4-10.4 (br, 2H), 8.5 (br, 1H), 8.02 (s, 1H), 7.45 (s,1H), 7.38 (s, 1H), 7.27 (br s, 1H), 7.1 (dd, 1H), 7.02 (d, 1H), 6.7 (d,1H), 5.3 (s, 2H), 4.0 (m, 1H), 2.8-3.8 (m, 14H), 2.32 (s, 3H), 2.28 (s,3H), 1.3-2.1 (m, 12H).

Synthesis of4-(5,6-dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid(127)

This compound is synthesized from 3,4-dimethylphenol analogously to themethod described for 106 (see example 55).

MS (ESI): 334 [M−H]⁻, 1H-NMR (DMSO-d₆): δ (ppm) 12.9 (br s, 1H), 11.55(s, 1H), 8.02 (s, 1H), 7.47 (s, 1H), 7.38 (s, 1H), 7.15 (dd, 1H), 7.0(m, 2H), 6.7 (d, 1H), 5.3 (s, 2H), 2.35 (s, 3H), 2.3 (s, 3H).

Example 1054-(5,6-Dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized from4-(5,6-dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid(127, see example 104) and amine 21 analogously to the method describedin example 1.

Yield: 96 mg (51%). MS (ESI): 545.5 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 8.09 (d, 1H), 8.05 (s, 1H), 7.22 (s, 1H), 7.18 (s, 1H),7.10 (dd, 1H), 7.0 (d, 1H), 6.88 (s, 1H), 6.7 (d, 1H), 5.28 (s, 2H),4.45 (d, 1H), 3.7 (m, 1H), 3.38 (m, 1H), 2.84 (m, 2H), 2.7 (m, 2H), 2.5(s, 3H), 2.38 (s, 3H), 2.35 (m, 4H), 1.95 (m, 4H), 1.7 (m, 4H), 1.45 (m,2H), 1.3 (m, 2H).

Example 1064-(5,6-Dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(5,6-dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid(127, see example 104) and amine 14 analogously to the method describedin example 1.

Yield: 105 mg (56%). MS (ESI): 559 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 10.6 (br, 2H), 8.5 (d, 1H), 8.02 (s, 1H), 7.45 (s, 1H),7.4 (s, 1H), 7.25 (d, 1H), 7.1 (dd, 1H), 7.02 (d, 1H), 6.7 (d, 1H), 5.29(s, 2H), 4.05 (m, 1H), 2.6-3.8 (m, 13H), 2.33 (s, 3H), 2.3 (s, 3H),1.75-2.2 (m, 8H), 0.93 (d, 3H).

Example 1074-(5,6-Dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(5,6-dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid(127, see example 104) and amine 50 analogously to the method describedin example 1.

Yield: 112 mg (56.8%). MS (ESI): 559 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 10.3-10.6 (br, 2H), 8.5 (d, 1H), 8.12 (s, 1H), 7.45 (s,1H), 7.38 (s, 1H), 7.25 (s, 1H), 7.1 (dd, 1H), 7.03 (d, 1H), 6.7 (d,1H), 5.3 (s, 2H), 5.05 (br, 1H), 2.9-4.1 (m, 13H), 2.35 (s, 3H), 2.28(s, 3H), 1.7-2.2 (m, 8H), 1.35/1.3 (d, 3H) (rotamers).

Example 1084-(5,6-Dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amidedihydrochloride

This compound is synthesized from4-(5,6-dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid(127, see example 104) and amine 56 analogously to the method describedin example 1.

Yield: 130 mg (68%). MS (ESI): 573 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 10.4-10.6 (br, 2H), 8.52 (d, 1H), 8.02 (s, 1H), 7.45 (s,1H), 7.4 (s, 1H), 7.25 (s, 1H), 7.12 (dd, 1H), 7.03 (d, 1H), 6.7 (d,1H), 5.3 (s, 2H), 5.1 (br, 1H), 4.05 (m, 1H), 2.8-3.9 (m, 13H), 2.32 (s,3H), 2.29 (s, 3H), 1.9-2.1 (m, 6H), 1.32 (d, 3H), 0.93 (d, 3H).

Example 109 4-(4-Ethoxy-phenyl)-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-(4-ethoxy-phenyl)-1H-indole-2-carboxylic acid, (preparationanalogously to 128, see example 141) and amine 50.

MS (ESI): 505.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.6 (s, 1H), 8.25 (d,1H), 7.56 (d, 2H), 7.36 (d, 1H), 7.31 (s, 1H), 7.2 (t, 1H), 7.05 (d,2H), 7.02 (d, 1H), 4.48 (m, 1H), 4.09 (q, 2H), 3.76 (m, 1H), 3.37 (m,1H), 2.58-2.96 (m, 5H), 1.85-2.43 (m, 6H), 1.42-1.83 (m, 6H), 1.37 (t,3H), 1.33 (m, 2), 0.93 (d, 3H).

Example 110 4-(4-Methoxy-phenyl)-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 1 from4-(4-methoxy-phenyl)-1H-indole-2-carboxylic acid, 128 (see example 141)and amine 50.

MS (ESI): 491 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.59 (s, 1H), 8.23 (d,1H), 7.56 (d, 2H), 7.34 (d, 1H), 7.31 (s, 1H), 7.2 (t, 1H), 7.06 (d,2H), 7.01 (d, 1H), 4.44 (d, 1H), 3.81 (s, 3H), 3.75 (m, 1H), 2.96 (m,1H), 2.6-2.95 (m, 5H), 2.04-2.4 (m, 5H), 1.92 (m, 1H), 1.2-1.85 (m, 8H),0.91 (d, 3H).

The 4-aryloxy-indole-2-carboxamides are generally prepared by a couplingof the 4-hydroxy-indole-2-carboxamides with the corresponding1-fluoro-2-nitro-benzenes (Reaction Scheme 15) Reaction Scheme 15:

Example 111 4-Phenoxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized analogously to Example 1 from4-phenoxy-1H-indole-2-carboxylic acid 129 (preparation see below) andamine 5.

Yield: 105 mg (41%) of a beige solid; MS (ESI): 459.4 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 11.7 (s, 1H), 8.22 (d, 1H), 7.34 (dd, 2H), 7.24 (d,1H), 7.04-7.15 (m, 3H), 6.95 (d, 2H), 6.55 (d, 1H), 3.72 (m, 1H), 2.85(m, 2H), 2.52-2.6 (m, 6H), 2.38 (m, 2H), 2.0 (t, 4H), 1.72 (m, 2H), 1.48(m, 8H).

Synthesis of 4-Phenoxy-1H-indole-2-carboxylic acid (129) (1) Step A:4-(2-Nitro-phenoxy)-1H-indole-2-carboxylic acid ethyl ester (130)

4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (0.5 g, 2.436 mmol)and 2-fluoro-nitro-benzene (0.257 ml, 2.436 mmol) are dissolved in 10 mlof dimethylformamide. After addition of potassium carbonate (0.67 g,4.87 mmol) the mixture is stirred over night at room temperature. Thenthe reaction mixture is evaporated under reduced pressure, dissolvedwith ethyl acetate and washed with water. The organic layers are driedover sodium sulfate and evaporated. The crude product is used in thenext step without further purification.

Yield: 0.72 g (91%) of a beige solid. MS (ESI): 325.2 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 12.15 (s, 1H), 8.1 (d, 1H), 7.6 (dd, 1H), 7.32 (m,2H), 7.25 (dd, 1H), 7.03 (d, 1H), 6.85 (m, 1H), 6.7 (d, 1H), 4.3 (q,2H), 1.3 (t, 3H).

(2) Step B: 4-(2-Amino-phenoxy)-1H-indole-2-carboxylic acid ethyl (131)

130 (0.5 g, 1.532 mmol) is dissolved in 100 ml of ethanol and, afteraddition of Pd—C (100 mg), the mixture is hydrogenated at roomtemperature for 3 hours. The mixture is filtrated over celite to removethe catalyst and evaporated.

Yield: 390 mg (86%) of a grey solid. MS (ESI): 297 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.95 (s, 1H), 7.13 (m, 2H), 7.0 (s, 1H), 6.88 (m,1H), 6.8 (dd, 1H), 6.75 (dd, 1H), 6.5 (m, 1H), 6.38 (m, 1H), 4.9 (br,2H), 4.3 (q, 2H), 1.3 (t, 3H).

(3) Step C: 4-Phenoxy-1H-indole-2-carboxylic acid ethyl ester (132)

Tert-butyl nitrite (0.2 ml, 1.687 mmol) is dissolved in 5 ml ofdimethylformamide and heated to 65° C. A solution of 131 (0.5 g, 1.687mmol) in 5 ml of dimethylformamide is added dropwise and the mixture isstirred of additional 10 minutes. The brown solution is cooled to roomtemperature, diluted with diethyl ether and washed with 2N HCl andbrine. The organic layers are dried over sodium sulphate and evaporated.The crude product (370 mg of a brown oil) is further purified byflash-chromatography (hexane/ethyl acetate 9:1).

Yield: 163 mg (34%) of a yellow solid; MS (ESI): 280.2 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 12.05 (s, 1H), 7.37 (d, 1H), 7.35 (d, 1H), 7.23 (m,2H), 7.1 (dd, 1H), 7.0 (d, 2H), 6.82 (s, 1H), 6.6 (d, 1H), 4.3 (q, 2H),1.3 (t, 3H).

(4) Step D: -Phenoxy-1H-indole-2-carboxylic acid (129)

132 (160 mg, 0.569 mmol) is dissolved in 5 ml of methanol and treatedwith a solution of LiOH (27.2 mg, 1.138 mmol) in 3 ml of water. Themixture is stirred at room temperature overnight. Since the reaction isnot complete (TLC), additional LiOH (30 mg, 1.25 mmol) is added and thestirring is continued for additional 18 h. After evaporation, the crudeproduct is acidified at 0° C. with 2M HCl and extracted with ethylacetate. The organic layers are dried over sodium sulphate andevaporated.

Yield: 146 mg (100%) of a yellow solid; MS (ESI): 253 [M]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 12.9 (s, 1H), 11.9 (s, 1H), 7.38 (d, 1H), 7.34 (d,1H), 7.2 (m, 2H), 7.12 (m, 1H), 7.0 (d, 2H), 6.75 (s, 1H), 6.58 (d, 1H).

Example 112 4-m-Tolyloxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)piperidin-4-yl]-amide

This compound is synthesized analogously to Example 1 from4-m-tolyloxy-1H-indole-2-carboxylic acid 133 (preparation see below) andamine 5.

Yield: 12 mg (11.3%) of a white solid; MS (ESI): 473.3 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 11.65 (s, 1H), 8.2 (d, 1H), 7.2 (m, 2H), 7.1 (m, 2H),6.88 (d, 1H), 6.78 (m, 1H), 6.7 (m, 1H), 6.54 (d, 1H), 3.72 (m, 1H),2.85 (m, 2H), 2.48-2.58 (m, 8H), 2.35 (m, 2H), 2.25 (s, 3H), 1.98 (m,2H), 1.75 (m, 2H), 1.48-1.55 (m, 8H).

Synthesis of 4-m-Tolyloxy-1H-indole-2-carboxylic acid (133) (1) Step A:4-(5-Methyl-2-nitro-phenoxy)-1H-indole-2-carboxylic acid ethyl ester(134)

4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (1 g, 4.87 mmol) and2-Fluoro-4-methyl-1-nitro-benzene (756 mg, 4.87 mmol) are dissolved in20 ml of dimethylformamide. After addition of potassium carbonate (1.3g, 9.74 mmol) the mixture is stirred over night at room temperature.Then the reaction mixture is evaporated under reduced pressure,dissolved with ethyl acetate and washed with water. The organic layersare dried over sodium sulfate and evaporated. The crude product is usedin the next step without further purification.

Yield: 1.59 g (96%) of a beige solid. MS (ESI): 341 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 12.15 (s, 1H), 7.98 (d, 1H), 7.3 (d, 1H), 7.25 (dd,1H), 7.15 (d, 1H), 6.88 (d, 1H), 6.63 (d, 1H), 4.3 (q, 2H), 2.28 (s,3H), 1.3 (t, 3H).

(2) Step B: 4-(2-Amino-5-methyl-phenoxy)-1H-indole-2-carboxylic acidethyl ester (135)

134 (1.3 g, 3.82 mmol) is dissolved in 250 ml of ethyl acetate and,after addition of Pd—C (200 mg), the mixture is hydrogenated at roomtemperature for 3 hours. The mixture is filtrated over celite to removethe catalyst and evaporated.

Yield: 1.12 g (95%) of a grey solid. MS (ESI): 311 [M+H]⁺]+, 1H-NMR(DMSO-d₆): δ (ppm) 11.95 (br, 1H), 7.13 (m, 2H), 7.03 (s, 1H), 6.72 (s,2H), 6.58 (s, 1H), 6.37 (m, 1H), 4.68 (br, 2H), 4.3 (q, 2H), 2.08 (s,3H), 1.3 (t, 3H).

(3) Step C: 4-m-Tolyloxy-1H-indole-2-carboxylic acid ethyl ester (136)

Tert-butyl nitrite (0.428 ml, 3.609 mmol) is dissolved in 5 ml ofdimethylformamide and heated to 65° C. A solution of 135 (1.1 g, 3.609mmol) in 5 ml of dimethylformamide is added dropwise and the mixture isstirred of additional 10 minutes. The brown solution is cooled to roomtemperature, diluted with diethyl ether and washed with 2N HCl andbrine. The organic layers are dried over sodium sulphate and evaporated.The crude product (930 mg of a brown oil) is further purified byflash-chromatography (hexane/ethyl acetate 7:3).

Yield: 520 mg (49%) of a yellow solid; MS (ESI): 294.2 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 12.0 (s, 1H), 7.18-7.24 (m, 3H), 6.92 (m, 1H), 6.82(m, 2H), 6.78 (dd, 1H), 6.58 (dd, 1H), 4.28 (q, 2H), 2.27 (s, 3H), 1.3(t, 3H).

(4) Step D: 4-m-Tolyloxy-1H-indole-2-carboxylic acid (133)

136 (520 mg, 1.761 mmol) is dissolved in 10 ml of methanol and treatedwith a solution of LiOH (84.3 mg, 3.52 mmol) in 5 ml of water. Themixture is stirred at room temperature for 18 hours. After evaporation,the crude product is acidified at 0° C. with 2M HCl and extracted withethyl acetate. The organic layers are dried over sodium sulphate andevaporated.

Yield: 460 mg (98%) of a beige solid; MS (ESI): 266.1 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 12.9 (s, 1H), 11.9 (s, 1H), 7.15-7.25 (m, 3H), 6.9(m, 1H), 6.84 (m, 1H), 6.78 (m, 2H), 6.57 (m, 1H), 2.27 (s, 3H).

Example 113 4-m-Tolyloxy-1H-indole-2-carboxylic acid{1-[2-(3-(RS)-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to Example 1 from4-m-Tolyloxy-1H-indole-2-carboxylic acid 133 (see example 112) andracemic amine 12.

Yield: 34 mg (21%) of a yellow solid; MS (ESI): 477.3 [M+H]⁺, 1H-NMR(80° C., DMSO-d₆): δ (ppm) 11.2 (s, 1H), 7.77 (d, 1H), 7.24 (dd, 1H),7.2 (dd, 1H), 7.1 (ss, 1H), 7.04 (s, 1H), 6.88 (d, 1H), 6.8 (m, 1H),6.75 (m, 1H), 6.54 (d, 1H), 3.75 (m, 1H), 3.5 (m, 1H), 2.7-2.9 (m, 4H),2.6 (m, 1H), 2.44 (m, 4H), 2.3 (s, 3H), 2.13 (m, 2H), 2.05 (m, 1H), 1.95(m, 1H), 1.7-1.85 (m, 3H), 1.55-1.65 (m, 3H), 1.4 (m, 1H), 1.15 (m, 1H).

Example 114 4-m-Tolyloxy-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to Example 1 from4-m-tolyloxy-1H-indole-2-carboxylic acid 133 (see example 112) and amine21.

Yield: 45 mg (28%) of a white solid; MS (ESI): 477 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.7 (s, 1H), 8.2 (d, 1H), 7.2 (m, 2H), 7.1 (m, 2H),6.88 (d, 1H), 6.78 (m, 1H), 6.7 (m, 1H), 6.54 (d, 1H), 4.47 (m, 1H),3.72 (m, 1H), 3.38 (m, 1H), 2.85 (m, 2H), 2.7 (m, 2H), 2.38 (m, 4H),2.28 (s, 3H), 1.98 (m, 4H), 1.63-1.75 (m, 4H), 1.5 (m, 2H), 1.35 (m,2H).

Example 115 4-p-Tolyloxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)piperidin-4-yl]-amide

This compound is synthesized analogously to Example 1 from4-p-tolyloxy-1H-indole-2-carboxylic acid 137 (preparation see below) andamine 5.

Yield: 12 mg (11.3%) of a white solid; MS (ESI): 473.3 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 11.65 (s, 1H), 8.18 (d, 1H), 7.05-7.2 (m, 5H), 6.85(d, 2H), 6.47 (m, 1H), 3.7 (m, 1H), 2.85 (m, 2H), 2.47-2.58 (m, 6H),2.35 (m, 2H), 2.25 (s, 3H), 1.98 (m, 2H), 1.75 (m, 2H), 1.48-1.55 (m,10H).

Synthesis of 4-p-Tolyloxy-1H-indole-2-carboxylic acid (137) (1) Step A:4-(3,5-Difluoro-2-nitro-phenoxy)-1H-indole-2-carboxylic acid ethyl ester(138)

4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (1 g, 4.87 mmol) and1-Fluoro-4-methyl-2-nitro-benzene (0.6 ml, 4.87 mmol) are dissolved in10 ml of dimethylformamide. After addition of potassium carbonate (1.3g, 9.74 mmol) the mixture is stirred over night at room temperature.Then the reaction mixture is evaporated under reduced pressure,dissolved with ethyl acetate and washed with water. The organic layersare dried over sodium sulfate and evaporated. The crude product (1.51 gof a brown oil) is further purified by flash-chromatography(hexane/ethyl acetate 9:1).

Yield: 570 mg (34%) of a white solid. MS (ESI): 341 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 12.1 (s, 1H), 7.88 (d, 1H), 7.45 (dd, 1H), 7.27 (d,1H), 7.22 (dd, 1H), 6.98 (d, 1H), 6.87 (s, 1H), 6.6 (d, 1H), 4.3 (q,2H), 2.35 (s, 3H), 1.3 (t, 3H).

(2) Step B: 4-(2-Amino-4-methyl-phenoxy)-1H-indole-2-carboxylic acidethyl ester (139)

138 (570 mg, 1.675 mmol) is dissolved in 150 ml of ethanol and, afteraddition of Pd—C (200 mg), the mixture is hydrogenated at roomtemperature for 2 hours. The mixture is filtrated over celite to removethe catalyst and evaporated.

Yield: 3.08 g (100%) of a brown oil. MS (ESI): 311 [M+H]⁺.

(3) Step C: 4-p-Tolyloxy-1H-indole-2-carboxylic acid ethyl ester (140)

Tert-butyl nitrite (0.176 ml, 1.48 mmol) is dissolved in 5 ml ofdimethylformamide and heated to 65° C. A solution of 139 (460 mg, 1.48mmol) in 5 ml of dimethylformamide is added dropwise and the mixture isstirred of additional 10 minutes. The brown solution is cooled to roomtemperature, diluted with diethyl ether and washed with 2N HCl andbrine. The organic layers are dried over sodium sulphate and evaporated.The crude product (420 mg of a brown oil) is further purified byflash-chromatography (hexane/ethyl acetate 9:1).

Yield: 70 mg (16%) of a yellow solid; MS (ESI): 294.2 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 12.0 (s, 1H), 7.15-7.24 (m, 4H), 7.4 (m, 2H), 6.85(d, 1H), 6.52 (dd, 1H), 4.3 (q, 2H), 2.28 (s, 3H), 1.3 (t, 3H).

(4) Step D: 4-p-Tolyloxy-1H-indole-2-carboxylic acid (137)

140 (70 mg, 0.237 mmol) is dissolved in 5 ml of methanol and treatedwith a solution of LiOH (11.4 mg, 0.474 mmol) in 3 ml of water. Themixture is stirred at room temperature for 18 hours. After evaporation,the crude product is acidified at 0° C. with 2M HCl and extracted withethyl acetate. The organic layers are dried over sodium sulphate andevaporated.

Yield: 60 mg (100%) of a beige solid; MS (ESI): 266.2 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 12.9 (s, 1H), 11.8 (s, 1H), 7.13-7.2 (m, 4H), 6.9 (m,2H), 6.77 (d, 1H), 6.52 (dd, 1H), 2.29 (s, 3H).

Example 116 4-p-Tolyloxy-1H-indole-2-carboxylic acid{1-[2-(3-(RS)-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to Example 1 from4-p-tolyloxy-1H-indole-2-carboxylic acid 137 (see example 115) andracemic amine 12.

Yield: 87 mg (49%) of a beige solid; MS (ESI): 475.3 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 11.65 (s, 1H), 8.2 (d, 1H), 7.08-7.2 (m, 5H), 6.87(d, 2H), 6.47 (d, 1H), 4.53 (d, 1H), 3.72 (m, 1H), 3.4 (m, 1H), 2.85 (m,3H), 2.65 (m, 1H), 2.37 (m, 4H), 2.28 (s, 3H), 1.98 (t, 2H), 1.7-1.85(m, 5H), 1.55 (m, 3H), 1.35 (m, 1H), 1.05 (m, 1H).

Example 117 4-p-Tolyloxy-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to Example 1 from4-p-tolyloxy-1H-indole-2-carboxylic acid 137 (see example 115) and amine21.

Yield: 80 mg (45%) of a beige solid; MS (ESI): 475.3 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 11.65 (s, 1H), 8.2 (d, 1H), 7.07-7.2 (m, 5H), 6.85(d, 2H), 6.47 (d, 1H), 4.48 (br, 1H), 3.72 (m, 1H), 3.4 (m, 1H), 2.85(m, 2H), 2.7 (m, 2H), 2.35 (m, 4H), 2.27 (s, 3H), 1.95-2.05 (m, 4H),1.65-1.75 (m, 4H), 1.5 (m, 2H), 1.35 (m, 2H).

Example 118 4-(3-Fluoro-phenoxy)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized analogously to Example 1 from4-(3-Fluoro-phenoxy)-1H-indole-2-carboxylic acid 141 (preparation seebelow) and amine 5.

Yield: 50 mg (28.3%) of a white solid; MS (ESI): 479.3 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.75 (s, 1H), 8.2 (d, 1H), 7.35 (dd, 1H), 7.28 (d,1H), 7.18 (dd, 1H), 7.05 (s, 1H), 6.9 (dd, 1H), 6.73-6.8 (m, 2H), 6.68(d, 1H), 3.72 (m, 1H), 2.85 (m, 2H), 2.5-2.58 (m, 6H), 2.35 (m, 2H),1.98 (m, 2H), 1.72 (m, 2H), 1.48-1.55 (m, 10H).

Synthesis of 4-p-Tolyloxy-1H-indole-2-carboxylic acid (141) (1) Step A:4-(3,5-Difluoro-2-nitro-phenoxy)-1H-indole-2-carboxylic acid ethyl ester(142)

4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (1 g, 4.87 mmol) and2,4-Difluoro-1-nitro-benzene (0.534 ml, 4.87 mmol) are dissolved in 20ml of dimethylformamide. After addition of potassium carbonate (1.3 g,9.74 mmol) the mixture is stirred over night at room temperature. Thenthe reaction mixture is evaporated under reduced pressure, dissolvedwith ethyl acetate and washed with water. The organic layers are driedover sodium sulfate and evaporated. The crude product is used in thenext step without further purification.

Yield: 1.63 g (97%) of a grey resin; MS (ESI): 343.1 [M−H]⁻.

(2) Step B: 4 4-(2-Amino-5-fluoro-phenoxy)-1H-indole-2-carboxylic acidethyl ester (143)

142 (1.6 g, 4.734 mmol) is dissolved in 250 ml of ethyl acetate and,after addition of Pd—C (200 mg), the mixture is hydrogenated at roomtemperature for 2 hours. The mixture is filtrated over celite to removethe catalyst and evaporated.

Yield: 1.41 g (95%) of a grey foam. MS (ESI): 315.2 [M+H]⁺.

(3) Step C: 4-(3-Fluoro-phenoxy)-1H-indole-2-carboxylic acid ethyl ester(144)

Tert-butyl nitrite (0.46 ml, 4.45 mmol) is dissolved in 5 ml ofdimethylformamide and heated to 65° C. A solution of 143 (1.4 g, 4.45mmol) in 5 ml of dimethylformamide is added dropwise and the mixture isstirred of additional 10 minutes. The brown solution is cooled to roomtemperature, diluted with diethyl ether and washed with 2N HCl andbrine. The organic layers are dried over sodium sulphate and evaporated.The crude product (1.0 g of a brown oil) is further purified byflash-chromatography (hexane/ethyl acetate 7:3).

Yield: 440 mg (33%) of a yellow solid; MS (ESI): 298.2 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 12.1 (s, 1H), 7.35 (dd, 1H), 7.3 (d, 1H), 7.25 (dd,1H), 6.92 (dd, 1H), 6.77-6.87 (m, 3H), 6.7 (d, 1H), 4.3 (q, 2H), 1.3 (t,3H).

(4) Step D: 4-(3-Fluoro-phenoxy)-1H-indole-2-carboxylic acid (141)

144 (440 mg, 1.47 mmol) is dissolved in 10 ml of methanol and treatedwith a solution of LiOH (70 mg, 1.47 mmol) in 5 ml of water. The mixtureis stirred at room temperature for 18 hours. After evaporation, thecrude product is acidified at 0° C. with 2M HCl and extracted with ethylacetate. The organic layers are dried over sodium sulphate andevaporated.

Yield: 420 mg (100%) of a yellow solid; MS (ESI): 270.1 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 12.95 (s, 1H), 11.9 (s, 1H), 7.35 (dd, 1H), 7.28 (d,1H), 7.18 (dd, 1H), 6.9 (dd, 1H), 6.77-6.85 (m, 2H), 6.75 (s, 1H), 6.7(d, 1H).

Example 119 4-(3-Fluoro-phenoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to Example 1 from4-(3-fluoro-phenoxy)-1H-indole-2-carboxylic acid 141 (see example 118)and amine 21.

Yield: 35 mg (20%) of a white solid; MS (ESI): 479 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 11.75 (s, 1H), 8.21 (d, 1H), 7.35 (dd, 1H), 7.29 (d,1H), 7.18 (dd, 1H), 7.05 (s, 1H), 6.9 (dd, 1H), 6.73-6.8 (m, 2H), 6.68(d, 1H), 4.49 (d, 1H), 3.72 (m, 1H), 3.4 (m, 1H), 2.85 (m, 2H), 2.7 (m,2H), 2.37 (m, 4H), 1.95 (m, 4H), 1.63-1.77 (m, 4H), 1.5 (m, 2H), 1.35(m, 2H).

Example 120 4-(4-Fluoro-phenoxy)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized analogously to Example 1 from4-(4-fluoro-phenoxy)-1H-indole-2-carboxylic acid 145 (preparation seebelow) and amine 5.

Yield: 86 mg (49%) of a white solid; MS (ESI): 477.3 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 11.75 (s, 1H), 8.2 (d, 1H), 7.14-7.24 (m, 5H), 7.0(m, 2H), 6.5 (d, 1H), 3.72 (m, 1H), 2.85 (m, 2H), 2.5-2.6 (m, 6H), 2.36(m, 2H), 1.98 (m, 2H), 1.72 (m, 2H), 1.48-1.57 (m, 10H).

Synthesis of 4-p-Tolyloxy-1H-indole-2-carboxylic acid (145) (1) Step A:4-(4-Fluoro-2-nitro-phenoxy)-1H-indole-2-carboxylic acid ethyl ester(146)

4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (0.92 g, 4.483 mmol)and 1,4-Difluoro-2-nitro-benzene (0.486 ml, 4.483 mmol) are dissolved in10 ml of dimethylformamide. After addition of potassium carbonate (1.2g, 8.96 mmol) the mixture is stirred over night at room temperature.Then the reaction mixture is evaporated under reduced pressure,dissolved with ethyl acetate and washed with water. The organic layersare dried over sodium sulfate and evaporated. The crude product is usedin the next step without further purification.

Yield: 1.45 g (94%) of a grey resin; MS (ESI): 343.1 [M−H]⁻]−, 1H-NMR(DMSO-d₆): δ (ppm) 12.15 (s, 1H), 8.08 (m, 1H), 7.55 (m, 1H), 7.3 (d,1H), 7.24 (dd, 1H), 7.15 (dd, 1H), 6.9 (s, 1H), 6.62 (d, 1H), 4.3 (q,2H), 1.32 (t, 3H).

(2) Step B: 4-(2-Amino-4-fluoro-phenoxy)-1H-indole-2-carboxylic acidethyl ester (147)

146 (1.5 g, 4.21 mmol) is dissolved in 200 ml of ethyl acetate and,after addition of Pd—C (200 mg), the mixture is hydrogenated at roomtemperature for 2 hours. The mixture is filtrated over celite to removethe catalyst and evaporated.

Yield: 1.31 g (99%) of a beige solid. MS (ESI): 313.2 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 11.95 (s, 1H), 7.12 (m, 2H), 7.05 (m, 1H), 6.75 (dd,1H), 6.58 (dd, 1H), 6.34 (m, 1H), 6.28 (dt, 1H), 5.25 (br, 2H), 4.3 (q,2H), 1.32 (t, 3H).

(3) Step C: 4-(4-Fluoro-phenoxy)-1H-indole-2-carboxylic acid ethyl ester(148)

Tert-butyl nitrite (0.46 ml, 4.45 mmol) is dissolved in 5 ml ofdimethylformamide and heated to 65° C. A solution of 147 (1.4 g, 4.45mmol) in 5 ml of dimethylformamide is added dropwise and the mixture isstirred of additional 10 minutes. The brown solution is cooled to roomtemperature, diluted with diethyl ether and washed with 2N HCl andbrine. The organic layers are dried over sodium sulphate and evaporated.The crude product (1.0 g of a brown oil) is further purified byflash-chromatography (hexane/ethyl acetate 7:3).

Yield: 440 mg (33%) of a yellow solid; MS (ESI): 298.2 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 12.05 (s, 1H), 7.2 (m, 4H), 7.05 (m, 2H), 6.85 (m,1H), 6.54 (d, 1H), 4.3 (q, 2H), 1.3 (t, 3H).

(4) Step D: 4-(4-Fluoro-phenoxy)-1H-indole-2-carboxylic acid (145)

148 (510 mg, 1.7 mmol) is dissolved in 10 ml of methanol and treatedwith a solution of LiOH (82 mg, 3.4 mmol) in 5 ml of water. The mixtureis stirred at room temperature for 18 hours. After evaporation, thecrude product is acidified at 0° C. with 2M HCl and extracted with ethylacetate. The organic layers are dried over sodium sulphate andevaporated.

Yield: 460 mg (100%) of a yellow solid; MS (ESI): 270.1 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 13.0 (s, 1H), 11.9 (s, 1H), 7.15-7.22 (m, 4H), 7.05(m, 2H), 6.78 (m, 1H), 6.55 (d, 1H).

Example 121 4-(4-Fluoro-phenoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to Example 1 from4-(4-fluoro-phenoxy)-1H-indole-2-carboxylic acid 145 (see example 120)and amine 21.

Yield: 66 mg (37%) of a white solid; MS (ESI): 479 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 11.7 (s, 1H), 8.2 (d, 1H), 7.1-7.24 (m, 5H), 7.0 (m,2H), 6.5 (d, 1H), 4.46 (br, 1H), 3.72 (m, 1H), 3.42 (m, 1H), 2.85 (m,2H), 2.7 (m, 2H), 2.38 (m, 4H), 2.0 (m, 4H), 1.64-1.77 (m, 4H), 1.53 (m,2H), 1.35 (m, 2H).

Example 122 4-(3,4-Difluoro-phenoxy)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized analogously to Example 1 from4-(3,4-Difluoro-phenoxy)-1H-indole-2-carboxylic acid 149 (preparationsee below) and amine 5.

Yield: 62 mg (36%) of a white solid; MS (ESI): 495.3 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 11.75 (s, 1H), 8.23 (d, 1H), 7.44 (m, 1H), 7.26 (d,1H), 7.14 (m, 1H), 7.0 (m, 1H), 6.80 (m, 1H), 6.56 (d, 2H), 3.72 (m,1H), 2.87 (m, 2H), 2.5-2.6 (m, 6H), 2.38 (m, 2H), 2.0 (m, 2H), 1.75 (m,2H), 1.47-1.55 (m, 10H).

Synthesis of 4-(3,5-Difluoro-phenoxy)-1H-indole-2-carboxylic acid (149)(1) Step A: 4-(3,5-Difluoro-2-nitro-phenoxy)-1H-indole-2-carboxylic acidethyl ester (150)

4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (1 g, 4.87 mmol) and1,2,4-Trifluoro-5-nitro-benzene (0.559 ml, 4.87 mmol) are dissolved in10 ml of dimethylformamide. After addition of potassium carbonate (1.3g, 9.74 mmol) the mixture is stirred over night at room temperature.Then the reaction mixture is evaporated under reduced pressure,dissolved with ethyl acetate and washed with water. The organic layersare dried over sodium sulfate and evaporated.

Yield: 1.79 g (100%) of a yellow foam. MS (ESI): 361.1 [M−H]⁻.

(2) Step B: 4-(2-Amino-4,5-difluoro-phenoxy)-1H-indole-2-carboxylic acidethyl ester (151)

150 (1.8 g, 4.87 mmol) is dissolved in 150 ml of ethyl acetate and,after addition of Pd—C (500 mg), the mixture is hydrogenated at roomtemperature for 2 hours. The mixture is filtrated over celite to removethe catalyst and evaporated.

Yield: 1.61 g (99%) of a brown foam. MS (ESI): 333.2 [M+H]⁺.

(3) Step C: 4-(3,4-Difluoro-phenoxy)-1H-indole-2-carboxylic acid ethylester (152)

Tert-butyl nitrite (0.575 ml, 4.85 mmol) is dissolved in 5 ml ofdimethylformamide and heated to 65° C. A solution of 151 (1.6 g, 4.85mmol) in 5 ml of dimethylformamide is added dropwise and the mixture isstirred of additional 10 minutes. The brown solution is cooled to roomtemperature, diluted with diethyl ether and washed with 2N HCl andbrine. The organic layers are dried over sodium sulphate and evaporated.The crude product (1.78 g of a brown oil) is further purified byflash-chromatography (hexane/ethyl acetate 9:1).

Yield: 380 mg (25%) of a slightly yellow solid; MS (ESI): 316.2 [M−H]⁻,1H-NMR (DMSO-d₆): δ (ppm) 12.1 (s, 1H), 7.45 (m, 1H), 7.27 (d, 1H), 7.2(dd, 1H), 7.05 (m, 1H), 6.98 (m, 1H), 6.95 (m, 1H), 6.55 (d, 1H), 4.3(q, 2H), 1.34 (t, 3H).

(4) Step D: 4-(3,4-Difluoro-phenoxy)-1H-indole-2-carboxylic acid (149)

152 (380 mg, 1.2 mmol) is dissolved in 10 ml of methanol and treatedwith a solution of LiOH (57 mg, 2.4 mmol) in 5 ml of water. The mixtureis stirred at room temperature for 18 hours. After evaporation, thecrude product is acidified at 0° C. with 2M HCl and extracted with ethylacetate. The organic layers are dried over sodium sulphate andevaporated.

Yield: 310 mg (90%) of a yellow solid; MS (ESI): 288.1 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 13.0 (s, 1H), 12.0 (s, 1H), 7.45 (m, 1H), 7.25 (d,1H), 7.18 (dd, 1H), 7.05 (m, 1H), 6.98 (m, 1H), 6.87 (s, 1H), 6.55 (d,1H).

Example 123 4-(3,5-Difluoro-phenoxy)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized analogously to Example 1 from4-(3,5-difluoro-phenoxy)-1H-indole-2-carboxylic acid 153 (preparationsee below) and amine 5.

Yield: 180 mg (33.2%) of a yellow solid; MS (ESI): 495.3 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 11.8 (s, 1H), 8.21 (d, 1H), 7.33 (d, 1H), 7.2 (dd,1H), 7.04 (d, 1H), 6.94 (m, 1H), 6.75 (d, 1H), 6.62 (m, 2H), 3.7 (m,1H), 2.85 (m, 2H), 2.47-2.58 (m, 6H), 2.36 (m, 2H), 1.98 (m, 2H), 1.75(m, 2H), 1.47-1.55 (m, 10H).

Synthesis of 4-(3,5-Difluoro-phenoxy)-1H-indole-2-carboxylic acid (153)(1) Step A: 4-(3,5-Difluoro-2-nitro-phenoxy)-1H-indole-2-carboxylic acidethyl ester (154)

4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (1 g, 4.87 mmol) and1,3,5-Trifluoro-2-nitro-benzene (0.57 ml, 4.87 mmol) are dissolved in 10ml of dimethylformamide. After addition of potassium carbonate (1.3 g,9.74 mmol) the mixture is stirred over night at room temperature. Thenthe reaction mixture is evaporated under reduced pressure, dissolvedwith ethyl acetate and washed with water. The organic layers are driedover sodium sulfate and evaporated.

Yield: 1.8 g (100%) of a yellow foam. MS (ESI): 361.2 [M−H]⁻.

(2) Step B: 4-(2-Amino-3,5-difluoro-phenoxy)-1H-indole-2-carboxylic acidethyl ester (155)

154 (1.8 g, 4.87 mmol) is dissolved in 150 ml of ethyl acetate and,after addition of Pd—C (500 mg), the mixture is hydrogenated at roomtemperature for 2 hours. The mixture is filtrated over celite to removethe catalyst and evaporated.

Yield: 1.53 g (94%) of a brown foam. MS (ESI): 333.2 [M+H]⁺.

(3) Step C: 4-(3,5-Difluoro-phenoxy)-1H-indole-2-carboxylic acid ethylester (156)

Tert-butyl nitrite (0.547 ml, 4.6 mmol) is dissolved in 5 ml ofdimethylformamide and heated to 65° C. A solution of 155 (1.5 g, 4.6mmol) in 5 ml of dimethylformamide is added dropwise and the mixture isstirred of additional 10 minutes. The brown solution is cooled to roomtemperature, diluted with diethyl ether and washed with 2N HCl andbrine. The organic layers are dried over sodium sulphate and evaporated.The crude product (1.5 g of a brown oil) is further purified byflash-chromatography (hexane/ethyl acetate 9:1).

Yield: 260 mg (17.8%) of a yellow solid; MS (ESI): 316.2 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 12.2 (s, 1H), 7.35 (d, 1H), 7.28 (dd, 1H), 6.95 (m,1H), 6.82 (d, 1H), 6.79 (d, 1H), 6.68 (dd, 1H), 4.3 (q, 2H), 1.3 (t,3H).

(4) Step D: 4-(3,5-Difluoro-phenoxy)-1H-indole-2-carboxylic acid (153)

156 (260 mg, 0.82 mmol) is dissolved in 10 ml of methanol and treatedwith a solution of LiOH (40 mg, 1.6 mmol) in 5 ml of water. The mixtureis stirred at room temperature for 18 hours. After evaporation, thecrude product is acidified at 0° C. with 2M HCl and extracted with ethylacetate. The organic layers are dried over sodium sulphate andevaporated.

Yield: 240 mg (100%) of a yellow solid;

Example 124 4-(3,5-Difluoro-phenoxy)-1H-indole-2-carboxylic acid{1-[2-(3—RS-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to Example 1 from4-(3,5-Difluoro-phenoxy)-1H-indole-2-carboxylic acid 153 (see example123) and racemic amine 12.

Yield: 38 mg (32%) of a white solid; MS (ESI): 499 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.8 (s, 1H), 8.25 (d, 1H), 7.33 (d, 1H), 7.2 (dd,1H), 7.04 (s, 1H), 6.92 (dd, 1H), 6.76 (d, 1H), 6.63 (d, 2H), 4.02 (d,1H), 3.72 (m, 1H), 3.4 (m, 1H), 2.8-2.9 (m, 3H), 2.67 (m, 2H), 2.38 (m,4H), 1.99 (m, 2H), 1.68-1.88 (m, 5H), 1.47-1.6 (m, 3H), 1.371 (m, 1H),1.05 (m, 1H).

Example 125 4-(3,5-Difluoro-phenoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to Example 1 from4-(3,5-Difluoro-phenoxy)-1H-indole-2-carboxylic acid 153 (see example123) and amine 21.

Yield: 23 mg (13%) of a white solid; MS (ESI): 497.2 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 11.79 (s, 1H), 8.22 (br, 1H), 7.32 (d, 1H), 7.2 (dd,1H), 7.04 (s, 1H), 6.9 (dd, 1H), 6.75 (d, 1H), 6.6 (d, 2H), 4.46 (s,1H), 3.72 (m, 1H), 3.39 (m, 1H), 2.83 (m, 2H), 2.67 (m, 2H), 2.35 (m,4H), 1.98 (m, 4H), 1.75 (m, 2H), 1.65 (m, 2H), 1.51 (m, 2H), 1.35 (m,2H).

Alternatively, the 4-alkoxy-indole-2-Carboxamides are Prepared as Shownin Reaction Scheme 16.

Reaction Scheme 1116:

Example 126 4-(6-Chloro-pyridin-2-yloxy)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized analogously to Example 1 from4-(6-Chloro-pyridin-2-yloxy)-1H-indole-2-carboxylic acid 157(preparation see below) and amine 5.

Yield: 85 mg (54%) of yellow crystals; MS (ESI): 494.3 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 11.8 (s, 1H), 8.2 (d, 1H), 7.85 (dd, 1H), 7.3 (d,1H), 7.2 (m, 2H), 6.95 (s, 1H), 6.9 (d, 1H), 6.8 (d, 1H), 3.7 (m, 1H),2.85 (m, 2H), 2.5-2.6 (m, 6H), 2.35 (m, 2H), 2.0 (t, 2H), 1.75 (m, 2H),1.5 (m, 10H).

Synthesis of 4-(6-Chloro-pyridin-2-yloxy)-1H-indole-2-carboxylic acid(157) (1) Step A: 4-Benzyloxy-indole-1,2-dicarboxylic acid 1-tert-butylester 2-ethyl ester (158)

4-Benzyloxy-1H-indole-2-carboxylic acid ethyl ester (10 g, 34 mmol) andDMAP (80 mg) are dissolved in 80 ml of ethyl acetate. BOC2O (8.9 g, 41mmol) dissolved in a small amount of ethyl acetate is added at roomtemperature. The mixture is stirred over night at room temperature. Thenthe reaction mixture is washed with 1 m aqueous tartaric acid, water andbrine. The organic layers are dried over sodium sulfate and evaporated.The crude product is used in the next step without further purification

Yield: 13.8 g (100%) of a yellow oil. 1H-NMR (CDCl₃): δ (ppm) 7.7 (d,1H), 7.3-7.5 (m, 7H), 6.75 (d, 1H), 5.2 (s, 2H), 4.4 (q, 2H), 1.7 (s,9H), 1.4 (t, 3H).

(2) Step B: 4-Hydroxy-indole-1,2-dicarboxylic acid 1-tert-butyl ester2-ethyl ester (159)

158 (8 g, 20 mmol) is dissolved in 80 ml of ethyl acetate and, afteraddition of 5% Pd—C (700 mg), the mixture is hydrogenated at roomtemperature for 7 hours. The mixture is filtrated over celite to removethe catalyst and evaporated. The solid is suspended in ether/hexane andfiltered.

Yield: 4.6 g (74%). 1H-NMR (CDCl₃): δ (ppm) 7.7 (d, 1H), 7.3 (m, 2H),6.7 (d, 1H), 5.5 (s, 1H), 4.4 (q, 2H), 1.7 (s, 9H), 1.4 (t, 3H).

(3) Step C: 4-(6-Chloro-pyridin-2-yloxy)-1H-indole-2-carboxylic acidethyl ester (160)

159 (500 mg, 1.6 mmol), 2,6-Dichloro-pyridine (360 mg, 24 mmol) aredissolved in 15 ml of dimethylformamide. After addition of potassiumcarbonate (340 mg, 24 mmol) and a catalytic amount Cu-powder the mixtureis heated to 160° C. for 3 hours. The reaction mixture is cooled to roomtemperature, diluted with ethyl acetate and washed with water. Theorganic layers are dried over sodium sulphate and evaporated. The crudeproduct is solved in dichloromethane and after evaporation crystallizedwith cyclohexane.

Yield: 300 mg (58%) of a beige solid. MS (ESI): 317.2 [M+H]⁺, 1H-NMR(CDCl3): δ (ppm) 9.2 (br, 1H), 7.7 (dd, 1H), 7.3 (m, 2H), 7.1 (m, 2H),6.95 (dd, 1H), 6.75 (d, 1H), 4.4 (q, 2H), 1.4 (t, 3H).

(4) Step D: 4-(6-Chloro-pyridin-2-yloxy)-1H-indole-2-carboxylic acid(157)

160 (100 mg, 0.315 mmol) is dissolved in 4 ml of methanol and treatedwith a solution of NaOH (1 ml, 2N). The mixture is stirred 1 hour atroom temperature. The reaction mixture is acidified with HCl (1 ml, 2N)and evaporated. The crude mixture is used in the next step withoutfurther purification.

Alternatively, the 4-alkoxy-indole-2-Carboxamides are Prepared as Shownin Reaction Scheme 17.

Reaction Scheme 17:

Example 127 4-Isobutoxy-1H-indole-2-carboxylic acid[1-(octahydro-quinolizin-1-yl)methyl)-piperidin-4-yl]-amidedihydrochloride

161 (preparation see below) (2.5 g, 7.1 mmol),octahydro-2H-chinolizin-1-ylmethanol (Lupinine) (1.2 g, 7.1 mmol) andethyldiisopropylamine (12.2 ml, 71 mmol) are dissolved in 10 ml ofpropionitril. After addition of cyanomethyl-trimethyl-phosphonium iodide(4.1 g, 17 mmol) the mixture is refluxed for 3 h. After cooling down toroom temperature, the mixture is diluted with ethyl acetate and washedwith potassium carbonate solution. The crude product 3.9 g of a brownoil) is crystallized from methanol.

Yield: 2 g (52%) of a white solid. MS (ESI): 467 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.42 (s, NH), 8.16 (d, NH), 7.22 (d, 1H), 7.02 (dd,1H), 6.96 (d, 1H), 6.45 (d, 1H), 3.83 (d, 2H), 3.75 (m, 1H), 3.49 (s,2H), 2.81 (m, 2H), 2.70 (m, 2H), 2.29 (m, 1H), 2.15-2.00 (m, 2H),1.95-1.73 (m, 7H), 1.72-1.27 (m, 9H), 1.26-1.10 (m, 2H), 1.05 (d, 6H).

Synthesis of 4-Isobutoxy-1H-indole-2-carboxylic acid(1-benzyl-piperidin-4-yl)-amide (161) (1) Step A:4-Isobutoxy-1H-indole-2-carboxylic acid (1-benzyl-piperidin-4-yl)-amide(161)

4-Isobutoxy-1H-indole-2-carboxylic acid 80 (4.7 g, 20.1 mmol,preparation see Example 8) and 1-benzyl-piperidin-4-ylamine (4.2 ml,20.1 mmol) are dissolved in 70 ml of DMF and after addition of TBTU (7.3g, 22.1 mmol) and ethyldiisopropylamine (13.8 ml, 80.4 mmol) the mixtureis stirred at room temperature for 2 h. Then the solvent is evaporatedat high vacuum. The residue is dissolved in ethyl acetate, washed withsaturated aqueous sodium hydrogen carbonate and brine. The organiclayers are dried over sodium sulfate and evaporated under reducedpressure.

Yield: 8.96 g of a beige solid. MS (ESI): 406.5 [M+H]⁺

(2) Step B: 4-Isobutoxy-1H-indole-2-carboxylic acid piperidin-4-ylamidehydrochloride (161)

161 (8.1 g, 20 mmol) is dissolved in 200 ml of ethanol and, afteraddition of Pd—C (200 mg) and 10 ml of 4M HCl the mixture ishydrogenated at room temperature for 3 hours. The mixture is filtratedover celite to remove the catalyst and evaporated.

Yield: 7.13 g (100%) of a white solid. MS (ESI): 316 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.5 (s, 1H), 8.42 (d, 1H), 7.25 (s, 2H), 7.04 (dd,1H), 6.95 (d, 1H), 6.45 (d, 1H), 4.0 (m, 1H), 3.83 (d, 2H), 3.22 (m,2H), 2.88 (m, 2H), 2.1 (m, 1H), 1.9 (m, 2H), 1.7 (m, 2H), 1.05 (d, 6H).

Example 128 4-Isobutoxy-1H-indole-2-carboxylic acid[1-(1-methyl-piperidin-3-yl)methyl)-piperidin-4-yl]-amide

This compound is synthesized from the compound 161 (see example 127) and(1-Methyl-piperidin-3-yl)-methanol analogously to the method describedin Example 127.

Yield: 60 mg (50%). MS (ESI): 427 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.45 (s, NH), 8.18 (d, NH), 7.21 (s, 1H), 7.02 (dd, 1H), 6.95 (d, 1H),6.45 (d, 1H), 3.85 (d, 2H), 3.75 (m, 1H), 2.88 (m, 1H), 2.78 (m, 2H),2.62 (m, 1H), 2.12 (s, 3H), 2.13-2.05 (m, 3H), 2.00-1.84 (m, 2H),1.84-1.40 (m, 10H), 1.05 (d, 6H), 0.82 (m, 1H).

Example 129 4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide

This compound is synthesized from4-cyclobutylmethoxy-1H-indole-2-carboxylic acid piperidin-4-ylamide, 162(preparation see below) and(1R,9aR)-1-(octahydro-quinolizin-1-yl)-methanol analogously to themethod described in example 127.

MS (ESI): 479.1 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.44 (s, 1H), 8.2 (d,1H), 7.2 (d, 1H), 7.03 (t, 1H), 6.96 (d, 1H), 6.47 (d, 1H), 4.04 (d,2H), 3.76 (m, 1H), 2.6-2.9 (m, 5H), 2.22-2.54 (m, 2H), 1.08-2.17 (m,26H).

Synthesis of 4-Cyclobutylmethoxy-1H-indole-2-carboxylic acidpiperidin-4-ylamide, 162 (1) Step A:4-[(4-Cyclobutylmethoxy-1H-indole-2-carbonyl)-amino]-piperidine-1-carboxylicacid tert-butyl ester, 163

To a solution of 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid (82)from example 34 (2.2 g, 8.97 mmol) in 20 ml of DCM is added4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.98 g, 9.87mmol), HOBT (1.37 g, 8.97 mmol), triethylamine (2.5 ml, 17.94 mmol) andEDC (1.72 g, 8.97 mmol). The mixture is stirred at room temperature overnight. It is then washed with 2N—NaOH and brine, dried over anhydroussodium sulphate and evaporated to give a yellow powder. The crudematerial is purified by chromatography on silicagel using hexane andEtOAc (from 0% to 20%).

Yield: 3.02 g (79%). MS (ESI): 426.3 [M−H]⁻, 1H-NMR (CDCl₃): δ (ppm)9.33 (s, 1H), 7.17 (t, 1H), 7.03 (d, 1H), 6.97 (s, 1H), 6.5 (d, 1H),6.12 (d, 1H), 4.13 (m, 4H), 4.07 (d, 2H), 2.78-2.97 (m, 4H), 1.88-2.25(m, 8H), 1.46 (s, 9H).

(2) Step B: 4-Cyclobutylmethoxy-1H-indole-2-carboxylic acidpiperidin-4-ylamide, 162

The tert-butyl ester (163) from above (3.02 g, 7.05 mmol) is dissolvedin 20 ml of dioxane. A 4M-solution of HCl in dioxane (14.1 ml, 56.4mmol) is added and the mixture is stirred for 24 hours. Evaporation gavethe hydrochloride as a white powder.

Yield: 2.93 g (>100%, not completely dry).

MS (ESI): 328.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.59 (s, 1H), 8.75(br m, 2H), 8.51 (d, 1H), 7.25 (s, 1H), 7.07 (t, 1H), 6.99 (d, 1H), 6.5(d, 1H), 4.1 (m, 1H), 4.05 (d, 2H), 3.25-3.45 (m, 2H), 3.02 (m, 2H),2.78 (m, 1H), 2.14 (m, 2H), 1.85-2.04 (m, 5H), 1.76 (m, 2H).

Example 130 4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid{1-[(S)-2-((3R,4R)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized from4-cyclobutylmethoxy-1H-indole-2-carboxylic acid piperidin-4-ylamide, 162(see example 129) and 2,2-dimethyl-propionic acid(3R,4R)-1-((R)-2-hydroxy-propyl)-3-methyl-piperidin-4-yl ester, 164(preparation see below) analogously to the method described in example127, followed by pivaloyl cleavage as described for amine 55.

MS (ESI): 483.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.43 (s, 1H), 8.2 (brs, 1H), 7.19 (s, 1H), 7.03 (t, 1H), 6.96 (d, 1H), 6.47 (d, 1H), 4.44 (m,1H), 4.04 (d, 2H), 3.73 (m, 1H), 2.58-2.96 (m, 7H), 2.04-2.41 (m, 6H),1.83-2.02 (m, 6H), 1.66-1.82 (m, 3H), 1.45-1.65 (m, 2H), 1.2-1.44 (m,2H), 0.91 (d, 3H), 0.86 (d, 3H).

(1) 2,2-Dimethyl-propionic acid(3R,4R)-1-(R)-2-hydroxy-propyl)-3-methyl-piperidin-4-yl ester (164)

A solution of piperidine 20 (3 g, 15.05 mmol) and (R)-2-methyl-oxirane(15.05 ml, 150.5 mmol) in 10 ml of ethanol is stirred for 24 hours in aclosed flask. The solvent is evaporated and the residue distilled in aKugelrohr apparatus (0.08 mbar, 80-90 C).

Yield: 3.82 g (99%). MS (ESI): 258.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)4.34 (br s, 1H), 4.24 (td, 1H), 3.70 (sextett, 1H), 2.79 (m, 2H),2.03-2.28 (m, 3H), 1.65-1.9 (m, 3H), 1.45 (qd, 1H), 1.14 (s, 9H), 1.02(d, 3H), 0.81 (d, 3H), [α]_(D)=−66.1 (c=1.5 in MeOH)

Example 131 4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4R,55)-3,4-dihydroxy-5-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized from4-cyclobutylmethoxy-1H-indole-2-carboxylic acid piperidin-4-ylamide, 162(see example 129) and amine 35 analogously to the method described in54, followed by cleavage of the protecting group.

MS (ESI): 499.4 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.47 (s, 1H), 8.28(br s, 1H), 7.23 (s, 1H), 7.04 (t, 1H), 6.99 (d, 1H), 6.49 (d, 1H), 4.07(m, 1H), 4.06 (d, 2H), 4.02 (m, 1H), 3.76 (m, 1H), 3.55 (m, 1H),2.58-2.96 (m, 6H), 2.25-2.4 (m, 3H), 1.83-2.15 (m, 11H), 1.66-1.82 (m,2H), 1.45-1.65 (m, 2H), 0.91 (d, 3H), 0.86 (d, 3H).

Example 132 4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid{1-[(R)-3-hydroxy-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized from4-cyclobutylmethoxy-1H-indole-2-carboxylic acid piperidin-4-ylamide, 162(see example 129) and 2,2-dimethyl-propionic acid(3S,4S)-1-((S)-2-hydroxy-3-trityloxy-propyl)-3-methyl-piperidin-4-ylester (60) analogously to the method described in 56, followed bysubsequent removal of the protection groups with sodium methylate and80% acetic acid.

MS (ESI): 499.5 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.44 (s, 1H), 8.22(d, 1H), 7.2 (d, 1H), 7.03 (t, 1H), 6.96 (d, 1H), 6.47 (d, 1H), 4.45 (d,1H), 4.28-4.45 (m, 1H), 4.04 (d, 2H), 3.7-3.8 (m, 1H), 3.42 (d, 2H),2.6-2.98 (m, 7H), 2.25-2.42 (m, 2H).1.15-2.18 (m, 16H), 0.86 (d, 3H).

Example 133 4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide

This compound is synthesized from4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid piperidin-4-ylamide,165 (preparation see below) and(1R,9aR)-1-(octahydro-quinolizin-1-yl)-methanol analogously to themethod described in example 127.

MS (ESI): 491.1 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.45 (s, 1H), 8.13(d, 1H), 7.82 (s, 1H), 7.68 (t, 1H), 7.22 (d, 1H), 7.05 (t, 1H), 6.98(d, 1H), 6.62 (s, 1H), 6.59 (d, 1H), 5.03 (s, 2H), 3.74 (m, 1H), 2.8 (m,2H), 2.69 (m, 2H), 2.43-2.53 (m, 1H), 2.27 (m, 1H), 2.02 (m, 1H),1.07-1.95 (m, 19H).

Synthesis of 4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acidpiperidin-4-ylamide (165) (1) Step A:4-{[4-(Furan-3-ylmethoxy)-1H-indole-2-carbonyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester (166)

To a solution of 4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid (95)from Example 33 (5 g, 19.44 mmol) in 10 ml of DCM is added4-amino-piperidine-1-carboxylic acid tert-butyl ester (3.89 g, 19.44mmol), HOBT (2.98 g, 19.44 mmol), triethylamine (5.4 ml, 38.88 mmol) andEDC (3.73 g, 19.44 mmol). The mixture is stirred at room temperatureover night. It is then washed with 2N—NaOH and brine, dried overanhydrous sodium sulphate and evaporated to give a yellow powder. Thecrude material is purified by chromatography on silicagel using DCM andEtOAc (from 0% to 10%).

Yield: 7.51 g (88%). MS (ESI): 438.3 [M−H]⁻, 1H-NMR (CDCl₃): δ (ppm)9.42 (s, 1H), 7.57 (s, 1H), 7.46 (s, 1H), 7.21 (t, 1H), 7.05 (d, 1H),6.96 (s, 1H), 6.6 (d, 1H), 6.55 (s, 1H), 6.08 (d, 1H), 5.07 (d, 2H),4.04-4.2 (overlapping m, 3H), 2.91 (m, 2H), 2.01 (m, 2H), 1.48 (s, 9H)1.42 (m, 2H).

(2) Step B: 4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acidpiperidin-4-ylamide (165)

The tert-butyl ester (166) from above (695 mg, 1.58 mmol) is dissolvedin 5 ml of dioxane. A 4M-solution of HCl in dioxane (3.2 ml, 12.8 mmol)is added and the mixture is stirred for 24 hours. Evaporation gave thehydrochloride as a white powder.

Yield: 595 mg (100%). MS (ESI): 340.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.65 (s, 1H), 9.0 (br m, 2H), 8.5 (d, 1H), 7.85 (s, 1H), 7.71 (s, 1H),7.3 (s, 1H), 7.09 (t, 1H), 7.02 (d, 1H), 6.62 (d, 1H), 6.64 (s, 1H),5.05 (d, 2H), 4.07 (m, 1H), 3.31 (m, 2H), 3.0 (m, 2H), 1.96 (m, 2H),1.78 (m, 2H).

Example 134 4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-((3R,4R)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized from4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid piperidin-4-ylamide,165 (see example 133) and 2,2-dimethyl-propionic acid(3R,4R)-1-((R)-2-hydroxy-propyl)-3-methyl-piperidin-4-yl ester, 164(preparation see example 130) analogously to the method described inexample 127, followed by pivaloyl cleavage as described for amine 55.

MS (ESI): 495.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.46 (s, 1H), 8.14(d, 1H), 7.82 (s, 1H), 7.68 (br s, 1H), 7.23 (s, 1H), 7.05 (t, 1H), 6.99(d, 1H), 6.62 (s, 1H), 6.6 (d, 1H), 5.03 (s, 2H), 4.43 (d, 1H), 3.72 (m,1H), 2.56-2.95 (m, 5H), 2.32 (m, 1H), 2.24 (m, 1H), 2.04-2.19 (m, 2H),1.9 (m, 2H), 1.67-1.79 (m, 3H), 1.43-1.61 (m, 2H), 1.21-1.41 (m, 3H),0.91 (d, 3H), 0.86 (d, 3H).

Example 135 4-(2-Methyl-thiazol-4-ylmethoxy)-1H-indole-2-carboxylic acid[1-(octahydro-quinolizin-1-yl)methyl)-piperidin-4-yl]-amide

This compound is synthesized from4-(2-methyl-thiazol-4-ylmethoxy)-1H-indole-2-carboxylic acidpiperidin-4-ylamide, (167, preparation see below) and(1R,9aR)-1-(octahydro-quinolizin-1-yl)-methanol analogously to themethod described in example 127.

MS (ESI): 522 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.5 (s, 1H), 8.15 (d,1H), 7.57 (s, 1H), 7.25 (s, 1H), 7.05 (dd, 1H), 6.98 (d, 1H), 6.62 (s,1H), 5.18 (s, 2H), 3.74 (m, 1H), 2.8 (m, 2H), 2.69 (m, 2H), 2.68 (s,3H), 2.43-2.53 (m, 1H), 2.27 (m, 1H), 2.02 (m, 1H), 1.07-1.95 (m, 19H).

Synthesis of 4-(2-methyl-thiazol-4-ylmethoxy)-1H-indole-2-carboxylicacid piperidin-4-ylamide (167) (1) Step A:(2-Methyl-thiazol-4-yl)-methanol (168)

2-Methyl-thiazole-4-carboxylic acid ethyl ester (966 mg, 5.64 mmol) isdissolved in 5 ml of diethylether and cooled to −78° C. A 1M solution oflithium aluminium hydride in THF (16.9 ml, 16.9 mmol) is added dropwiseand the mixture is stirred for 3.5 h at −78° C. The mixture is quenchedat this temperature with a saturated solution of sodium sulphate and isallowed to warm up to room temperature, followed by extraction withether and evaporation.

Yield: 670 mg (92%). MS (ESI): 130.0 [M−H]⁻, 1H-NMR (CDCl₃): δ (ppm)7.20 (s, 1H), 5.27 (dd, 1H), 4.50 (d, 2H), 2.62 (s, 3H).

(2) Step B: 4-(2-Methyl-thiazol-4-ylmethoxy)-indole-1,2-dicarboxylicacid 1-tert-butyl ester 2-ethyl ester (169)

(2-Methyl-thiazol-4-yl)-methanol (168, 670 mg, 5.2 mmol) is dissolved in12 ml of dry THF under argon, followed by addition of4-Hydroxy-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester(102, see example 42, 1.58 g, 5.2 mmol), triphenylphosphine (1.63 g, 6.2mmol).) and the solution is cooled to 0° C. A 40% solution of ethylazadicarboxylate in toluene (2.7 ml, 6.2 mmol) is added dropwise and themixture is stirred for 2.5 h at 0° C. The solvents are removed underreduced pressure and the residue is dissolved in ethyl acetate andwashed with sodium hydrogencarbonate solution and brine. The organiclayers are dried over sodium sulphate, filtrated and evaporated. Thecrude product is purified by flash chromatography (silica gel, ethylacetate/hexanes 3:7)

Yield: 1.75 g (81%). MS (ESI): 417.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)7.67 (s, 1H), 7.55 (d, 1H), 7.41 (dd, 1H), 7.27 (s, 1H), 6.99 (d, 1H),5.27 (s, 2H), 4.31 (q, 2H), 2.68 (s, 3H), 1.57 (s, 9H), 1.32 (t, 3H).

(3) Step C: 4-(2-Methyl-thiazol-4-ylmethoxy)-1H-indole-2-carboxylic acid(170)

4-(2-Methyl-thiazol-4-ylmethoxy)-indole-1,2-dicarboxylic acid1-tert-butyl ester 2-ethyl ester (169) (1.75 g, 4.2 mmol) is dissolvedin 20 ml of ethanol. After addition of a 0.5M aqueous sodium hydroxidesolution (33.6 ml, 16.8 mmol) the solution is heated to 60° C. andstirred at this temperature for 18 h. Then the reaction mixture isevaporated and the residue is dissolved in ethyl acetate. AT 0° C. concHCl is added until a pH of 11s reached. The organic phase is washed withwater and brine. The organic layers are dried over sodium sulphate,filtrated. The product crystallized upon evaporation and could befiltrated off.

Yield: 1.21 g (100%). MS (ESI): 289.0 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.76 (br s, 1H), 7.62 (s, 1H), 7.14 (dd, 1H), 7.07 (s, 1H), 7.02 (d,1H), 6.66 (d, 1H), 5.22 (s, 2H), 2.68 (s, 3H).

(4) Step D:4-{[4-(2-Methyl-thiazol-4-ylmethoxy)-1H-indole-2-carbonyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester (171)

4-(2-Methyl-thiazol-4-ylmethoxy)-1H-indole-2-carboxylic acid (170) (1.21g, 4.2 mmol) is dissolved in 10 ml of DMF and the solution is cooled to0° C. After addition of Huenigs base (2.16 ml, 12.6 mmol),piperidin-4-yl-carbamic acid tert-butyl ester (3) (841 mg, 4.2 mmol) andPyBOP (2.4 g, 4.6 mmol) the mixture is stirred at room temperature for18 h. Ethyl acetate is added followed by concentrated sodium hydroxide,until a pH of 11 is reached. The organic layer is washed with brine,dried over sodium sulphate and evaporated under reduced pressure. Thecrude product is purified by flash-chromatography (silica gel, ethylacetate/cyclohexane 1:1).

Yield: 1.58 g (80%). MS (ESI): 471.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.58 (br s, 1H), 8.25 (d, 1H), 7.61 (s, 1H), 7.27 (s, 1H), 7.09 (dd,1H), 7.02 (d, 1H), 6.63 (d, 1H), 5.18 (s, 2H), 3.93 (m, 3H), 2.85 (m,2H), 2.69 (s, 3H), 1.78 (m, 2H), 1.4 (s, 9H), 1.38 (m, 2H).

(5) Step E: 4-(2-Methyl-thiazol-4-ylmethoxy)-1H-indole-2-carboxylic acidpiperidin-4-ylamide (167)

171 from above (1.58 g, 3.36 mmol) is dissolved in a 4M solution of HClin dioxane (32 ml, 128 mmol) and stirred for 45 min at room temperature.Then the reaction mixture is evaporated, dissolved in ethyl acetate andconc sodium hydroxide is added until a pH of 11 is reached. The organiclayer is washed with brine, dried over sodium sulphate and evaporatedunder reduced pressure.

Yield: 1.28 g (100%). %). MS (ESI): 371.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ(ppm) 11.56 (br, 1H), 8.28 (d, 1H), 7.61 (s, 1H), 7.3 (s, 1H), 7.09 (dd,1H), 7.02 (d, 1H), 6.62 (d, 1H), 5.19 (s, 2H), 3.90 (m, 1H), 3.07 (m,2H), 2.70 (s, 3H), 2.62-2.75 (m, 2H), 1.72-1.85 (m, 3H), 1.4-1.55 (m,2H).

Example 136 4-(Benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-(3,4-dihydroxy-5-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized from4-(benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acidpiperidin-4-ylamide, 172 (preparation see below) and amine 35analogously to the method described in 54, followed by cleavage of theprotecting group.

MS (ESI): 561 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.48 (s, 1H), 8.16 (s,1H), 8.15 (d, 1H), 7.72 (d, 1H), 7.61 (d, 1H), 7.35 (dd, 1H), 7.29 (dd,1H), 7.19 (s, 1H), 7.09 (dd, 1H), 7.01 (d, 1H), 6.71 (d, 1H), 5.35 (s,2H), 4.04 (d, 1H), 3.98 (m, 1H), 3.72 (m, 1H), 3.53 (m, 1H), 2.50-2.90(m, 7H), 2.24-2.38 (m, 2H), 1.88-2.08 (m, 3H), 1.66-1.78 (m, 3H),1.45-1.58 (m, 2H), 0.86 (d, 3H), 0.83 (d, 3H).

Synthesis of 4-(Benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acidpiperidin-4-ylamide (172) (1) Step A:4-{[4-(Benzofuran-3-ylmethoxy)-1H-indole-2-carbonyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester (173)

To a ice-cold solution of4-(benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (105, see example50) (200 mg, 0.651 mmol) in 2 ml of dimethylformamide is added Huenigsbase (334 ul, 1.95 mmol). After stirring at 0° C. for 10 min,4-amino-piperidine-1-carboxylic acid tert-butyl ester (130 mg, 0.651mmol) and PyBOP (356 mg, 0.684 mmol) are added subsequently. The mixtureis stirred at room temperature over night. It is then diluted with ethylacetate, washed with 1N—NaOH and brine, dried over anhydrous sodiumsulphate and evaporated to give 980 mg of a lightbrown oil. The crudematerial is purified by chromatography on silicagel using cyclohexaneand ethylacetate (1:1).

Yield: 318 mg (100%). MS (ESI): 488.2 [M−H]⁻, 1H-NMR (CDCl₃): δ (ppm)9.15 (s, 1H), 7.77 (s, 1H), 7.72 (d, 1H), 7.55 (d, 1H), 7.38 (dd, 1H),7.3 (dd, 1H), 7.23 (d, 1H), 7.08 (d, 1H), 6.91 (s, 1H), 6.7 (d, 1H),5.96 (d, 1H), 5.34 (s, 2H), 4.04-4.2 (overlapping m, 3H), 2.91 (m, 2H),2.01 (m, 2H), 1.48 (s, 9H), 1.40 (m, 2H).

(2) Step B: 4-(Benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acidpiperidin-4-ylamide (172)

The tert-butyl ester (173) from above (318 mg, 0.65 mmol) is dissolvedin a 4M-solution of HCl in dioxane (6 ml, 1.2 mmol) and stirred for 1hour at room temperature. Evaporation gave the hydrochloride as a whitepowder, which is dissolved in water, treated with conc NaOH solution at0° C. to an pH of 11 and extracted with ethyl acetate. The organiclayers are washed with brine, dried over sodium sulphate and evaporated.

Yield: 248 mg (98%) of a light yellow solid. MS (ESI): 390.2 [M+H]⁺.

Example 137 4-(5-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid {1-[2-(3,4-dihydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized from4-(5-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acidpiperidin-4-ylamide (174, preparation see below) and amine 34analogously to the method described for 54, followed by cleavage of theprotecting group.

MS (ESI): 565 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.52 (s, 1H), 8.28 (s,1H), 7.68 (dd, 1H), 7.52 (d, 1H), 7.23 (s, 1H), 7.21 (dd, 1H), 7.11 (dd,1H), 7.03 (d, 1H), 6.72 (d, 1H), 5.35 (s, 2H), 4.19 (m, 1H), 4.13 (d,1H), 3.73 (m, 1H), 3.52 (br s, 1H), 3.44 (br s, 1H), 2.9 (m, 3H), 2.52(m, 2H), 2.33 (m, 3H), 2.11 (m, 1H), 2.03 (dd, 1H), 1.84 (dd, 1H), 1.75(d, 1H), 1.45-1.65 (m, 5H), 0.9 (d, 3H).

Synthesis of 4-(5-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid piperidin-4-ylamide (174) (1) Step A:4-{[4-(5-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carbonyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester (175)

To a solution of4-(5-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (113,see example 60, 160 mg, 0.49 mmol) is dissolved in 1.5 ml of DMF andcooled to 0° C. After addition of Huenigs base (252 ul, 1.5 mmol) themixture is stirred for 15 min, then piperidin-4-yl-carbamic acidtert-butyl ester (3, 98.5 mg, 0.49 mmol) is added, followed by PyBOP(269 mg, 0.51 mmol). The mixture is stirred at room temperature for 18h. Then the mixture is diluted with ethyl acetate, washed 1N sodiumhydroxide solution and brine. The organic layers are dried over sodiumsulfate and evaporated under reduced pressure. The crude product (581mg) is purified by flash-chromatography (silica gel, cyclohexane/ethylacetate

Yield: 250 mg (100%). MS (ESI): 506.2 [M−H]⁻.

(2) Step B: 4-(5-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid piperidin-4-ylamide (174)

The tert-butyl ester (175) from above (250 mg, 0.49 mmol) is dissolvedin a 4M-solution of HCl in dioxane (4 ml, 16 mmol) and the mixture isstirred for 1 h at room temperature. Evaporation gave the hydrochlorideas a yellow solid, which is dissolved in 5 ml of water and the pH isadjusted to 11 by addition of conc sodium hydroxide. The solution isextracted with ethyl acetate, the organic layers are washed with brineand dried over sodium sulphate. Evaporation gave 200 mg (100%) of awhite solid. %).

MS (ESI): 408.2 [M+H]⁺.

Example 138 4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid {1-[2-(3,4-dihydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized from4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acidpiperidin-4-ylamide, (176, preparation see below) and amine 34analogously to the method described for 54, followed by cleavage of theprotecting group.

MS (ESI): 581 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.5 (br s, 1H), 8.28(s, 1H), 8.17 (d, 1H), 7.79 (s, 1H), 7.68 (d, 1H), 7.39 (d, 1H), 7.22(s, 1H), 7.10 (dd, 1H), 7.03 (d, 1H), 6.7 (d, 1H), 5.36 (s, 2H), 4.18(m, 1H), 4.12 (d, 1H), 3.72 (m, 1H), 3.52 (m, 1H), 3.45 (m, 1H),2.45-2.9 (m, 4H), 2.33 (m, 4H), 1.88-2.14 (m, 3H), 1.73 (m, 2H),1.42-1.65 (m, 4H), 0.89 (d, 3H).

Synthesis of 4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid piperidin-4-ylamide (176) (1) Step A:4-{[4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carbonyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester (177)

This compound is synthesized from4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (113,see example 60) and amine 3 analogously to the method described for 175.

Yield: 270 mg (60%). MS (ESI): 522 [M−H]⁻, 1H-NMR (DMSO-d₆): δ (ppm)11.58 (m, 1H), 8.28 (s, 1H), 8.20 (d, 1H), 7.8 (s, 1H), 7.69 (d, 1H),7.4 (d, 1H), 7.2 (s, 1H), 7.11 (dd, 1H), 7.03 (d, 1H), 6.72 (d, 1H),5.36 (s, 2H), 3.93 (m, 3H), 2.7-2.9 (m, 2H), 1.76 (d, 2H), 1.4 (s, 9H),1.29-1.42 (m, 2H).

(2) Step B: 4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid piperidin-4-ylamide (176)

This compound is synthesized from 177 analogously to the methoddescribed for 175.

MS (ESI): 424.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.38 (s, 1H), 8.14(s, 1H), 8.02 (d, 1H), 7.66 (s, 1H), 7.55 (d, 1H), 7.27 (d, 1H), 7.09(s, 1H), 6.98 (dd, 1H), 6.91 (d, 1H), 6.59 (d, 1H), 5.23 (s, 2H), 3.68(m, 1H), 2.8 (m, 1H), 2.37 (m, 3H), 1.57 (m, 1H), 1.25 (m, 3H).

Example 139 4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[(9S,9aS)-1-(octahydro-pyrido[2,1-c][1,4]oxazin-9-yl)methyl]-piperidin-4-yl}-amide

This compound is synthesized from the compound 176 (see example 138) and(9RS,9aSR)-1-(octahydro-pyrido[2,1-c][1,4]oxazin-9-yl)-methanol (63)analogously to the method described in example 127.

Yield: 7.7 mg (12%) of a white solid. MS (ESI): 575/577 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.5 (s, 1H), 8.11 (d, 1H), 7.78 (d, 1H), 7.67 (d,1H), 7.38 (dd, 1H), 7.18 (d, 1H), 7.10 (m, 1H), 7.03 (d, 1H), 6.70 (d,1H), 5.36 (s, 2H), 3.75-3.60 (m, 2H), 3.50-3.30 (m, 4H), 2.80-2.55 (m,2H), 2.60-2.50 (m, 2H), 2.32 (d, 2H), 2.10-1.65 (m, 9H), 1.60-1.40 (m,3H), 1.35-1.20 (m, 2H).

Example 140 4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid{1-[(8S,8aS)-1-(hexahydro-pyrrolo[2,1-c][1,4]oxazin-8-yl)methyl]-piperidin-4-yl}-amide

This compound is synthesized from the compound 176 (see example 138) and(9RS,9aSR)-1-(octahydro-pyrido[2,1-c][1,4]oxazin-9-yl)-methanol (67)analogously to the method described in example 127.

Yield: 82 mg (14.6%) of a white solid. MS (ESI): 563/565 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.5 (s, 1H), 8.25 (s, 1H), 8.10 (d, 1H), 7.78 (d,1H), 7.67 (d, 1H), 7.38 (bd, 1H), 7.19 (s, 1H), 7.10-7.00 (m, 2H), 6.70(d, 1H), 5.35 (s, 2H), 4.00 (m, 1H), 3.90 (m, 1H), 3.75-3.60 (m, 2H),3.40-3.30 (m, 2H), 2.95-2.70 (m, 1H), 2.40-2.20 (m, 2H), 2.10-1.70 (m,8H), 1.55-1.25 (m, 4H), 1.15 (t, 1H), 1.07 (t, 1H).

Example 141 4-(4-Methoxy-phenyl)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide

This compound is synthesized from the compound 178 (preparation seebelow) and octahydro-2H-chinolizin-1-ylmethanol analogously to themethod described in example 127.

Yield: 350 mg (33.7%). MS (ESI): 501 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.6 (s, 1H), 8.22 (d, 1H), 7.56 (d, 2H), 7.37 (d, 1H), 7.31 (m, 1H),7.20 (dd, 1H), 7.07 (d, 2H), 7.01 (d, 1H), 3.81 (s, 3H), 3.75 (m, 1H),3.16 (d, 1H), 2.80 (m, 2H), 2.67 (m, 2H), 2.46 (dd, 1H), 2.28 (m, 1H),1.1-2.1 (m, 19H).

Synthesis of 4-(4-Methoxy-phenyl)-1H-indole-2-carboxylic acidpiperidin-4-ylamide (178) (1) Step A:4-(4-Methoxy-phenyl)-1H-indole-2-carboxylic acid (128)

4-Bromo-1H-indole-2-carboxylic acid (5 g, 20.8 mmol) and4-methoxy-phenyl-boronic acid (3.2 g, 20.8 mmol) are dissolved in1-propanol (100 ml) and the mixture is flushed with argon for 30 min.Then bis(triphenylphosphin)palladium(II)chloride (200 mg, 1 mmol) andNa2CO3 (4.4 g, 40.2 mmol) are added and the reaction mixture is stirredat 85° C. for 3 h. After cooling down to room temperature, ethyl acetateand 2M HCl are added. The organic layers are dried over sodium sulphate.Evaporation gave 6 g of an beige solide, which is further purified bycrystallisation from ethyl acetate.

Yield: 4.7 g (84%). MS (ESI): 266 [M−H]⁻.

(2) Step B: 4-(4-Methoxy-phenyl)-1H-indole-2-carboxylic acid(1-benzyl-piperidin-4-yl)-amide (179)

128 (4.7 g, 17.6 mmol) and 1-benzyl-piperidin-4-ylamine (3.3 g, 17.6mmol) are dissolved in DMF (70 ml) and after addition of TBTU (6.4 g,19.4 mmol) and ethyldiisopropylamine (12 ml, 70.4 mmol) the mixture isstirred at room temperature for 2 h. Then the solvent is evaporated athigh vacuum. The residue is dissolved in ethyl acetate washed withsaturated aqueous sodium hydrogen carbonate and brine. The organiclayers are dried over sodium sulfate and evaporated under reducedpressure. The crude mixture is crystallized from methanol.

Yield: 4.1 g (53%). MS (ESI): 440 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.6(s, 1H), 8.26 (d, 1H), 7.56 (d, 2H), 7.38 (d, 1H), 7.15-7.35 (m, 7H),7.08 (d, 2H), 7.01 (d 1H), 4.07 (m, 1H), 3.81 (s, 3H), 3.47 (s, 2H), 2.8(m, 2H), 2.04 (m, 2H), 1.77 (m, 2H), 1.58 (m, 2H).

(3) Step C: 4-(4-Methoxy-phenyl)-1H-indole-2-carboxylic acidpiperidin-4-ylamide (178)

179 (4 g, 9.1 mmol) is dissolved in 100 ml of methanol, flushed withargon and, after addition of Pd—C (100 mg) and 2M HCl (5.5 ml, 11 mmol),the mixture is hydrogenated at room temperature for 3 h. The mixture isfiltrated over celite and evaporated.

Yield: 1 g of a white solid (29%). MS (ESI): 350 [M+H]⁺.

Example 142 4-(4-Ethoxy-phenyl)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide

This compound is synthesized from the compound 180 (preparation seebelow) and octahydro-2H-chinolizin-1-ylmethanol analogously to themethod described in example 127.

Yield: 23 mg (16.2%). MS (ESI): 515 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.67 (s, 1H), 8.28 (d, 1H), 7.56 (d, 2H), 7.33 (d, 1H), 7.3 (m, 1H),7.20 (dd, 1H), 7.0-7.07 (m, 3H), 4.08 (q, 2H), 3.77 (m, 1H), 2.80 (dd,2H), 2.67 (m, 2H), 2.46 (dd, 1H), 2.28 (dd, 1H), 2.01 (dd, 1H), 1.36 (t,3H), 1.1-2.1 (m, 19H).

Synthesis of 4-(4-Ethoxy-phenyl)-1H-indole-2-carboxylic acidpiperidin-4-ylamide (180)

This compound has been synthesized from 4-ethoxy-phenyl-boronic acidanalogously to the method described in the synthesis of 178 (see example141).

MS (ESI): 364 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.64 (s, 1H), 8.28 (d,1H), 7.55 (d, 2H), 7.35 (d, 1H), 7.31 (s, 1H), 7.19 (dd, 1H), 7.06 (d,2H), 7.02 (d, 1H), 4.09 (q, 2H), 3.81 (m, 1H), 3.4 (m, 1H), 2.92 (m,2H), 2.46 (m, 2H), 1.77 (m, 2H), 1.4 (m, 2H), 1.37 (t, 3H).

Example 143 4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide

This compound is synthesized from4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acidpiperidin-4-ylamide (181, preparation see below) and amine 164analogously to the method described for 54, followed by cleavage of theprotecting group.

MS (ESI): 504 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.7 (s, 1H), 8.48 (brs, 1H), 8.28 (d, 1H), 7.97 (d, 1H), 7.41 (d, 1H), 7.36 (s, 1H), 7.24(dd, 1H), 7.09 (d, 1H), 6.96 (d, 1H), 4.44 (d, 1H), 3.93 (s, 3H),3.68-3.82 (m, 1H), 2.61-2.96 (m, 6H), 2.04-2.39 (m, 4H), 1.85-1.96 (m,2H), 1.66-1.82 (m, 3H), 1.45-1.65 (m, 2H), 1.2-1.44 (m, 2H), 0.91 (d,3H), 0.86 (d, 3H).

Synthesis of 4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acidpiperidin-4-ylamide (181) (1) Step A:4-[(4-Bromo-1H-indole-2-carbonyl)-amino]-piperidine-1-carboxylic acidtert-butyl ester (182)

4-Bromo-1H-indole-2-carboxylic acid (3 g, 12.5 mmol) is dissolved in 30ml of DMF and the solution is cooled to 0° C. After addition of Huenigsbase (6.4 ml, 37.5 mmol), the mixture is stirred for 15 min. Thenpiperidin-4-yl-carbamic acid tert-butyl ester 3 (2.5 g, 12.5 mmol) isadded, followed by PyBOP (7.2 g, 13.7 mmol). The reaction mixture isstirred for 18 h at room temperature. Then ethyl acetate is added andconc sodium hydroxide until a pH of 11 is reached. The organic layersare washed with brine, dried over sodium sulphate and evaporated. Thecrude product is further purified by flash-chromatography (silica gel,ethyl acetate/cyclohexane 1:1)

Yield: 5.13 g (97%). MS (ESI): 420, 422 [M−H]⁻, 1H—NMR (DMSO-d₆): δ(ppm) 11.9 (m, 1H), 8.48 (d, 1H), 7.45 (d, 1H), 7.27 (d, 1H), 7.21 (s,1H), 7.11 (dd, 1H), 2.86 (m, 2H), 1.81 (m, 2H), 1.42 (s, 9H), 1.42 (m,2H).

(2) Step B:4-{[4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carbonyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester (183)

An argon stream is bubbled through a solution of 182 from above (500 mg,1.2 mmol) and 2-methoxy-5-pyridine boronic acid (181 mg, 1.2 mmol) in 4ml of 1-propanol for 15 min. Then 2M aqueous sodium carbonate solution(1.2 ml, 2.4 mmol) and bis(triphenylphosphine)palladium-(II)-chloride(50 mg, 0.07 mmol) are added and the reaction mixture is stirred at 85°C. for 3 h. Then the mixture is cooled to 0° C. and ethyl acetate andconcentrated sodium hydroxide solution is added until a pH of 11 isreached. The solution is washed with brine and the organic layers aredried over sodium sulfate and evaporated. The crude product is purifiedby flash-chromatography (silica gel, cyclohexane/ethyl acetate 7:3).

Yield: 290 mg (69%). MS (ESI): 451.2 [M+H]⁺, 1H-NMR (CDCl₃): δ (ppm) 9.3(s, 1H), 8.53 (s, 1H), 7.96 (d, 1H), 7.46 (d, 1H), 7.38 (dd, 1H), 7.17(d, 1H), 6.98 (s, 1H), 6.86 (d, 1H), 6.12 (d, 1H), 4.13 (m, 2H), 4.08(s, 3H), 2.91 (m, 2H), 2.01 (m, 2H), 1.48 (s, 9H) 1.42 (m, 2H), 1.27 (m,1H).

(3) Step C: 4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acidpiperidin-4-ylamide (181)

183 from above (370 mg, 0.82 mmol) is dissolved in a 4M solution of HClin dioxane (7.5 ml, 30 mmol) and stirred for 1 h at room temperature.Then the reaction mixture is evaporated, dissolved in ethyl acetate andconc sodium hydroxide is added until a pH of 11 is reached. The organiclayer is washed with brine, dried over sodium sulphate and evaporatedunder reduced pressure.

Yield: 300 mg (100%). MS (ESI): 351.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.74 (m, 1H), 8.51 (s, 1H), 8.35 (d, 1H), 8.00 (d, 1H), 7.44 (d, 1H),7.41 (s, 1H), 7.27 (dd, 1H), 7.11 (d, 1H), 7.00 (d, 1H), 3.95 (s, 3H),3.84 (m, 1H), 2.96 (m, 2H), 2.31 (m, 1H), 2.01 (m, 2H), 1.75 (m, 2H),1.4 (m, 2H).

Example 144 4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized from4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acid[1-(2-hydroxy-ethyl)-piperidin-4-yl]-amide (184, preparation see below)and 2,2-Dimethyl-propionic acid (3S,4S)-3-methyl-piperidin-4-yl ester(17) analogously to the method described in example 150, followed bycleavage of the protecting group.

MS (ESI): 492 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.70 (s, 1H), 8.48 (brs, 1H), 8.30 (d, 1H), 7.97 (dd, 1H), 7.42 (d, 1H), 7.36 (s, 1H), 7.24(t, 1H), 7.09 (d, 1H), 6.97 (d, 1H), 4.47 (d, 1H), 3.92 (s, 3H), 3.75(m, 1H), 2.70-2.90 (m, 5H), 2.31-2.41 (m, 4H), 1.86-2.04 (m, 3H),1.66-1.82 (m, 3H), 1.46-1.62 (m, 3H), 1.3-1.44 (m, 2H), 0.86 (d, 3H).

Synthesis of 4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acid[1-(2-hydroxy-ethyl)-piperidin-4-yl]-amide (184)

4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acidpiperidin-4-ylamide (181), 150 mg, 0.43 mmol) is dissolved in 3 ml ofethanol under argon. After addition of sodium carbonate (182 mg, 1.7mmol) and 2-bromo-ethanol (61 ul, 0.85 mmol), the reaction mixture isstirred at 80° C. for 13 h. The mixture is diluted with methylenechloride, filtrated and the filtrate is evaporated. Evaporation underreduced pressure gave 128 mg of crude product, which is further purifiedby Flash-chromatography (dichloro methane/methanol/25% ammonia (90:9:1).Yield: 90 mg (53%). MS (ESI): 395.2 [M+H]⁺.

Example 145 4-p-Tolyloxy-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide

This compound is synthesized from the compound 185 (preparation seebelow) and octahydro-2H-chinolizin-1-ylmethanol analogously to themethod described in example 127.

Yield: 86 mg (34.9%). MS (ESI): 501 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.7 (s, 1H), 8.2 (d, 1H), 7.2 (d, 2H), 7.15 (d, 2H), 7.1 (s, 1H), 6.85(d, 2H), 6.47 (d, 1H), 3.72 (m, 1H), 2.8 (dd, 2H), 2.70 (d, 2H), 2.45(m, 1H), 2.3 (s, 3H), 2.28 (m, 1H), 2.03 (dd, 1H), 1.1-2.1 (m, 19H).

Synthesis of 4-p-tolyloxy-1H-indole-2-carboxylic acidpiperidin-4-ylamide (185) Reaction Scheme 18:

(1) Step A: 4-p-tolyloxy-1H-indole-2-carboxylic acid(1-benzyl-piperidin-4-yl)-amide (186)

4-p-tolyloxy-1H-indole-2-carboxylic acid (137) (850 mg, 3.2 mmol) and4-amino-N-benzylpiperidine (605 mg, 3.2 mmol) are dissolved in 5 ml ofDMF and after addition of TBTU (1.2 g, 3.5 mmol) andethyldiisopropylamine (2.2 ml, 12.8 mmol) the mixture is stirred at roomtemperature for 2 h. Then the mixture is evaporated at high vacuum. Theresidue is dissolved in ethyl acetate and washed with saturatedNaHCO3-solution and brine. The organic layers are dried over Na2SO4,filtrated and evaporated under reduced pressure. Yield: 1.47 g (100%) ofa yellow foam. MS (ESI): 438 [M−H]⁻.

(2) Step B: 4-p-Tolyloxy-1H-indole-2-carboxylic acid piperidin-4-ylamide(185)

Pd—C (1 g) is placed into a flask filled with argon and covered withmethanol. 186 (1.4 g, 3.2 mmol) is dissolved in 100 ml of methanol and1.6 ml of 2M HCl and added. After hydrogenation at room temperature for5 h the mixture is filtrated over celite and evaporated.

Yield: 1.1 g (96%) of a white foam. MS (ESI): 350 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.75 (s, 1H), 8.43 (d, 1H), 7.2 (d, 1H), 7.1-7.2 (m,4H), 6.85 (d, 2H), 6.47 (d, 1H), 4.05 (m, 1H), 3.26 (m, 2H), 2.90 (m,2H), 2.73 (s, 1H), 2.28 (s, 3H), 1.9 (m, 2H), 1.7 (m, 2H).

Alternatively, the Branched indole-2-Carboxamides Could be Prepared asShown in Reaction Scheme 19.

Reaction Scheme 19:

Example 146 4-Isobutoxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-1S-methyl-ethyl)-piperidin-4-yl]-amide

(1) Step A: 4-Isobutoxy-1H-indole-2-carboxylic acid[1-(2R-hydroxy-propyl)-piperidin-4-yl]-amide (187)

A solution of the hydrochloride of 4-isobutoxy-1H-indole-2-carboxylicacid piperidin-4-ylamide

(161) from Example 127 (300 mg, 0.85 mmol) in 5 ml of ethanol andtriethylamine (0.472 ml, 3.4 mmol) is treated with R(+)-propylene oxide(0.59 ml, 4.25 mmol) and stirred at room temperature in a sealed vesselfor 14 hours. Another portion of R(+)-propylene oxide (0.59 ml, 4.25mmol) is added and stirring continued for 24 hours. The solvents arethen evaporated. The crude is re-dissolved in DCM and washed with2N—NaOH and brine. The organic layer is dried over anhydrous sodiumsulphate and evaporated to give a white powder.

Yield: 290 mg (91%). MS (ESI): 374.1 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.45 (s, 1H), 8.22 (d, 1H), 7.22 (s, 1H), 7.03 (t, 1H), 6.97 (d, 1H),6.45 (d, 1H), 4.25 (br s, 1H), 3.84 (d, 2H), 3.75 (overlapping m, 2H),2.87 (m, 2H), 1.98-2.39 (m, 5H), 1.76 (m, 2H) 1.58 (m, 2H), 1.05 (m,9H).

(2) Step B: 4-Isobutoxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-1S-methyl-ethyl)-piperidin-4-yl]-amide

The alcohol (187) from above (100 mg, 0.27 mmol) is mixed with azepane(0.033 ml, 0.297 mmol), DIEA (0.227 ml, 1.35 mmol) andcyanomethyl-triphenyl phosphonium iodide (156 mg, 0.648 mmol) in 2 ml ofpropionitrile. The suspension is heated at 90° C. for 3 hours. Theresulting solution is cooled, diluted with EtOAc, washed with 2N—NaOHand brine, dried over anhydrous sodium sulphate and evaporated. Thecrude material is purified by chromatography on silicagel using DCM(saturated with ammonia) and MeOH (from 0% to 10%).

Yield: 74 mg (61%). MS (ESI): 455.4 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.43 (s, 1H), 8.2 (d, 1H), 7.22 (s, 1H), 7.02 (t, 1H), 6.96 (d, 1H),6.44 (d, 1H), 3.84 (d, 2H), 3.72 (br m, 1H), 2.52-2.95 (m, 8H), 2.15-2.4(m, 3H), 2.1 (m, 1H), 1.77 (m, 2H), 1.45-1.67 (m, 10H) 1.05 (d, 6H),0.95 (d, 3H).

Example 147 4-Isobutoxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-1R-methyl-ethyl)-piperidin-4-yl]-amide

The title compound is prepared as described in Example 83 from4-isobutoxy-1H-indole-2-carboxylic acid piperidin-4-ylamide (161),S(−)-propylene oxide and azepane. Intermediate4-Isobutoxy-1H-indole-2-carboxylic acid[1-(2S-hydroxy-propyl)-piperidin-4-yl]-amide (188) and final product hadMS and NMR spectra identical to the (R)-enantiomers of Example 146.

Example 148 4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid[1-(2S-azepan-1-yl-propyl)-piperidin-4-yl]-amide

S(−)-propylene oxide (21.2 ml, 302.5 mmol) and azepam (3.41 ml, 30.25mmol) are mixed in 10 ml of ethanol and stirred in a sealed vessel for24 hours. The solvents are then evaporated and the crude oil of1-azepan-1-yl-propan-2S-ol (189) is used as such without furtherpurification. Yield: 2.25 g (47%).

The alcohol (189) from above (63 mg, 0.405 mmol) is mixed with4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid piperidin-4-ylamide(165, see example 133) from step B (100 mg, 0.27 mmol), DIEA (0.227 ml,1.35 mmol) and cyanomethyl-triphenyl phosphonium iodide (193 mg, 0.81mmol) in 2 ml of propionitrile. The suspension is heated at 90° C. for 3hours. The resulting solution is cooled, diluted with EtOAc, washed with2N—NaOH and brine, dried over anhydrous sodium sulphate and evaporated.The crude material is purified by chromatography on silicagel using DCM(saturated with ammonia) and MeOH (from 0% to 10%).

Yield: 45 mg (35%). MS (ESI): 479.1 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.46 (s, 1H), 8.14 (d, 1H), 7.82 (s, 1H), 7.68 (s, 1H), 7.22 (s, 1H),7.05 (t, 1H), 6.99 (d, 1H), 6.62 (s, 1H), 6.59 (d, 1H), 5.03 (d, 2H),3.72 (m, 1H), 2.75-2.95 (m, 3H), 2.58 (m, 4H), 2.33 (m, 1H), 2.0-2.2 (m,2H), 1.92 (m, 1H), 1.74 (m, 2H), 1.45-1.6 (m, 10H), 0.91 (d, 3H).

Example 149 4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid[1-(2R-azepan-1-yl-propyl)-piperidin-4-yl]-amide

The title compound is prepared from4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid piperidin-4-ylamide(165) as described in Example 133 using R(+)-propylene oxide instead ofthe (S)-enantiomer.

MS and NMR spectra are identical to its enantiomeric example 148.

Alternatively, the 4-alkoxy-indole-2-Carboxamides are Prepared as Shownin Reaction Scheme 20.

Reaction Scheme 20:

Example 150 4-Isobutoxy-1H-indole-2-carboxylic acid{1-[2-(3,6-dihydro-2H-pyridin-1-yl)-ethyl]-piperidin-4-yl}-amide

1,2,5,6-Tetrahydropyridine (25.4 μl, 0.279 mmol), cyanomethyl-triphenylphosphonium iodide (162.5 mg, 0.6686 mmol) and Hünig's base (171 μl, 1mmol) are added subsequently to a suspension of 190 (preparation seebelow) (100 mg, 0.279 mmol) in 4 ml of propionitril. The mixture isstirred for 2 h at 100° C., then diluted with ethyl acetate, washed with1N sodium hydroxide solution and brine and dried over sodium sulfate.Evaporation gave 138 mg of crude product, which is further purified bypreparative HPLC (RP, acetonitrile/water).

Yield: 55 mg (47%). MS (ESI): 443.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.45 (s, 1H), 8.2 (d, 1H), 7.23 (d, 1H), 7.04 (t, 1H), 6.97 (d, 1H),6.45 (d, 1H), 4.5 (d, 1H), 3.85 (d, 2H) 3.74 (m, 1H), 3.41 (m, 1H), 2.88(m, 2H), 2.71 (m, 2H), 2.38 (m, 4H), 2.1 (m, 1H), 2.0 (m, 4H), 1.76 (m,2H), 1.68 (m, 2H), 1.55 (m, 2H), 1.35 (m, 2H), 1.06 (d, 6H).

Synthesis of 4-Isobutoxy-1H-indole-2-carboxylic acid[1-(2-hydroxy-ethyl)-piperidin-4-yl]-amide (190) (1) Step A:[1-(2-Hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester(191)

Piperidin-4-yl-carbamic acid tert-butyl ester (5 g, 25 mmol) isdissolved in 100 ml of ethanol. After addition of sodium carbonate (10.6g, 100 mmol), 2-bromo-ethanol (3.55 ml, 50 mmol) is added dropwise. Thereaction mixture is refluxed for 16 h and then evaporated. The residueis dissolved in 100 ml of dichloromethane and filtrated. The residue iswashed with DCM. The combined filtrates are evaporated, which afforded10.1 g of a yellow oil, which is further purified by flashchromatography (silicagel, DCM/methanol/conc. ammonia 90:9:1).

Yield: 4.02 g (66%) of a white solid. MS (ESI): 443.3 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.45 (s, 1H), 8.2 (d, 1H), 7.23 (d, 1H), 7.04 (t,1H), 6.97 (d, 1H), 6.45 (d, 1H), 4.5 (d, 1H), 3.85 (d, 2H) 3.74 (m, 1H),3.41 (m, 1H), 2.88 (m, 2H), 2.71 (m, 2H), 2.38 (m, 4H), 2.1 (m, 1H), 2.0(m, 4H), 1.76 (m, 2H), 1.68 (m, 2H), 1.55 (m, 2H), 1.35 (m, 2H), 1.06(d, 6H).

(2) Step B: 2-(4-Amino-piperidin-1-yl)-ethanol (192)

Compound 191 (4.02 g, 16.46 mmol) are treated with 4M HCl in dioxane (60ml, 240 mmol) and the mixture is stirred at room temperature for 1 h.The white precipitate is filtered off, washed with ether and dried underhigh vacuum. The mother liquor is concentrated and treated with ether.The white solid is filtered off and dried under high vacuum.

Yield: 3.42 g (95.9%). MS (ESI): 443.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.45 (s, 1H), 8.2 (d, 1H), 7.23 (d, 1H), 7.04 (t, 1H), 6.97 (d, 1H),6.45 (d, 1H), 4.5 (d, 1H), 3.85 (d, 2H) 3.74 (m, 1H), 3.41 (m, 1H), 2.88(m, 2H), 2.71 (m, 2H), 2.38 (m, 4H), 2.1 (m, 1H), 2.0 (m, 4H), 1.76 (m,2H), 1.68 (m, 2H), 1.55 (m, 2H), 1.35 (m, 2H), 1.06 (d, 6H).

(3) Step C: 4-Isobutoxy-1H-indole-2-carboxylic acid[1-(2-hydroxy-ethyl)-piperidin-4-yl]-amide (190)

4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8, 1g, 4.29 mmol) is suspended in 5 ml of DMF, cooled to 0° C. and treatedwith Hünig's Base (1.46 ml, 8.58 mmol). The mixture is stirred for 15min at 0° C. In a separate reaction flask, compound 192 (931 mg, 4.29mmol) in 10 ml of DMF is cooled to 0° C., treated with 10M aqueoussodium hydroxide solution (0.858 ml, 8.58 mmol) and stirred for 15 minat this temperature. This solution is added to the above mentionedmixture, followed by benzotriazol-1-yl-oxytripyrrolidinphosphoniumhexafluorophosphate (PyBOP, 2.34 g, 4.5 mmol) and stirred for 4 h atroom temperature. The reaction mixture is diluted with ethyl acetate andwashed with 2N sodium hydroxide solution, water and brine. Evaporationgave a semisolid, yellow crude product, which is treated with ether,filtered of and washed with ether.

Yield: 657 mg (83%). MS (ESI): 443.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.45 (s, 1H), 8.2 (d, 1H), 7.23 (d, 1H), 7.04 (t, 1H), 6.97 (d, 1H),6.45 (d, 1H), 4.5 (d, 1H), 3.85 (d, 2H) 3.74 (m, 1H), 3.41 (m, 1H), 2.88(m, 2H), 2.71 (m, 2H), 2.38 (m, 4H), 2.1 (m, 1H), 2.0 (m, 4H), 1.76 (m,2H), 1.68 (m, 2H), 1.55 (m, 2H), 1.35 (m, 2H), 1.06 (d, 6H).

Example 151 4-Isobutoxy-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-azepan-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 150 from4-isobutoxy-1H-indole-2-carboxylic acid[1-(2-hydroxy-ethyl)piperidin-4-yl]-amide, 190 and azepan-4-ol.

Yield: 36 mg (80%). MS (ESI): 457 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.45 (s, 1H), 8.19 (d, 1H), 7.23 (s, 1H), 7.02 (t, 1H), 6.96 (d, 1H),6.44 (d, 1H), 4.35 (d, 1H), 3.84 (d, 2H) 3.80-3.62 (m, 2H), 3.29 (s,1H), 2.88 (d, 2H), 2.68-2.30 (m, 8H), 2.14-2.06 (m, 1H), 2.0 (t, 2H),1.83-1.34 (m, 9H), 1.05 (d, 6H).

Example 152 4-Isobutoxy-1H-indole-2-carboxylic acid{1-[2-(3-amino-azepan-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized analogously to example 150 from4-isobutoxy-1H-indole-2-carboxylic acid[1-(2-hydroxy-ethyl)piperidin-4-yl]-amide, 190 and azepan-3-ylamine.

Yield: 48 mg (38%). MS (ESI): 456.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.5 (s, 1H), 8.27 (d, 1H), 7.24 (s, 1H), 7.05 (t, 1H), 6.97 (d, 1H),6.46 (d, 1H), 3.84 (d, 2H), 3.80-3.70 (m, 1H), 2.89 (m, 2H), 2.79 (m,1H), 2.68-2.62 (m, 1H), 2.60-2.52 (m, 4H), 2.43-2.27 (m, 3H), 2.15-2.05(m, 1H), 2.05-1.95 (m, 2H), 1.78-1.72 (m, 2H), 1.70-1.68 (m, 2H),1.60-1.50 (m, 6H), 1.43-1.35 (m, 1H), 1.32-1.22 (m, 1H), 1.05 (d, 6H).

Example 153 4-Isobutoxy-1H-indole-2-carboxylic acid{1-[2-(3-fluoro-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

To a suspension of 190 (see example 150) (100 mg, 0.28 mmol),3-fluoropiperidine hydrochloride (43 mg, 0.208 mmol) and DIEA (0.189 ml,1.12 mmol) in 0.5 ml of propionitrile is added cyanomethyl-triphenylphosphonium iodide (81 mg, 0.336 mmol). The mixture is heated at 90° C.for 14 hours. The resulting solution is then diluted with EtOAc (20 ml)and washed twice with saturated sodium bicarbonate, dried over sodiumsulfate and evaporated. The crude product is further purified bypreparative HPLC.

Yield: 30 mg (24%). MS (ESI): 445.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.43 (s, 1H), 8.19 (d, 1H), 7.22 (s, 1H), 7.02 (t, 1H), 6.96 (d, 1H),6.45 (d, 1H), 4.45-4.7 (m, 1H), 3.84 (d, 2H), 3.74 (m, 1H), 2.88 (m,2H), 2.76 (m, 1H), 2.18-2.48 (m, 8H), 2.1 (m, 1H), 2.0 (m, 2H), 1.34-1.9(m, 7H), 1.05 (d, 6H).

Example 154 4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid [4-(2-piperidin-1-yl-ethyl)-phenyl]-amide

This compound is synthesized analogously to example 150 from4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid[4-(2-hydroxy-ethyl)-phenyl]-amide (193, preparation see below) andpiperidine.

Yield: 140 mg (67%). MS (ESI): 528/530 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm)11.69 (s, 1H), 10.00 (s, 1H), 8.28 (s, 1H), 7.85-7.35 (m, 6H), 7.25-7.00(m, 4H), 6.75 (d, 1H), 5.40 (2, 2H), 2.70 (m, 4H), 2.60-2.20 (m, 4H),1.55-1.40 (m, 6H).

Synthesis of 4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid [4-(2-hydroxy-ethyl)-phenyl]-amide (193)

This compound is synthesized analogously to example 42 from4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (97) and2-(4-amino-phenyl)-ethanol.

Yield: 1.59 g (69%) of a white solid. MS (ESI): 461/463 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.68 (s, 1H), 9.99 (s, 1H), 8.27 (s, 1H), 7.80 (d,1H), 7.70-7.60 (m, 3H), 7.46 (d, 1H), 7.39 (dd, 1H), 7.20-7.10 (m, 3H),7.06 (d, 1H), 6.75 (d, 1H), 5.37 (s, 2H) 4.59 (m, 1H), 3.57 (m, 2H),2.67 (t, 2H).

Example 155 4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylicacid {4-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-phenyl}-amide

This compound is synthesized analogously to example 154 from4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid[4-(2-hydroxy-ethyl)-phenyl]-amide (193) and 2,2-dimethyl-propionic acidpiperidin-4-yl ester, followed by removal of the protective group bysodium methylate.

Yield: 38 mg (34.9%). MS (ESI): 528/530 [M+H]⁺, 1H-NMR (DMSO-d₆): δ(ppm) 11.68 (s, 1H), 8.27 (s, 1H), 7.63 (d, 1H), 7.70-7.60 (m, 3H), 7.45(d, 1H), 7.38 (dd, 1H) (s, 1H), 7.20-7.00 (m, 4H), 6.75 (d, 1H), 5.37(s, 2H), 4.49 (d, 1H), 3.42 (m, 1H), 2.80-2.60 (m, 4H), 2.45-2.40 (m,1H), 2.10-1.95 (m, 3H), 1.75-1.65 (m, 2H), 1.45-1.30 (m, 2H).

The 4-aryl-indole-2-carboxamides are generally prepared by a Suzukicoupling of the 4-bromo-indole-2-carboxamides with the correspondingaryl-boronic acids (Reaction Scheme 15).

Reaction Scheme 21:

Example 156 4-Phenyl-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)piperidin-4-yl]-amide

Bromindole 194 (preparation see below) 150 mg, 0.335 mmol),Phenyl-boronic acid (82 mg, 0.67 mmol) and triphenylphosphine (26.4 mg,0.112 mmol) are dissolved in 10 ml of toluene. After addition of 1 ml ofethanol, argon is flushed through the mixture for 30 min. ThenPd(II)acetate (3 mg, 13.4 μmol) and 2M aqueous sodium carbonate (0.67ml, 1.34 mmol) are added. The mixture is stirred under reflux for 3 h.After cooling down to r.t., the mixture is treated with 30 ml of ethylacetate and 5% aqueous NaHCO3 solution and filtrated over celite. Theorganic layer is separated and evaporation under reduced pressure gave170 mg of crude product, which is further purified by flashchromatography (silica gel, ethyl acetate/methanol conc. NH3 90:10:2)and crystallization from ethyl acetate.

Yield: 45 mg (30%) of a white solid; MS (ESI): 445.4 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.64 (s, 1H), 8.25 (d, 1H), 7.63 (d, 2H), 7.50 (dd,2H), 7.40 (m, 2H), 7.31 (s, 1H), 7.23 (dd, 1H), 7.08 (d, 1H), 3.73 (m,1H), 2.85 (m, 2H), 2.57 (m, 6H), 2.36 (m, 2H), 1.99 (m, 2H), 1.74 (m,2H), 1.52 (m, 10H).

(1) 4-Bromo-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide (194)

4-Bromo-1H-indole-2-carboxylic acid (1.5 g, 3.1 mmol),1-(2-azepan-1-yl-ethyl)-piperidin-4-ylamine tri-hydrochloride (S) (2.1g, 3.1 mmol) and DIEA (4.3 ml, 12.4 mmol) are dissolved under argonatmosphere in DMF (25 ml). TBTU (2.3 g, 3.4 mmol) is added at roomtemperature. The reaction mixture is stirred for 2 h at r.t., evaporatedunder high vacuum, dissolved in ethyl acetate and washed twice with 5%aqueous NaHCO3 solution. The organic layers are dried over sodiumsulfate. Evaporation under reduced pressure gave 1.3 g (93%) of a beigesolid.

MS (ESI): 447.1, 449.1 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.9 (s, 1H),8.4 (d, 1H), 7.4 (d, 1H), 7.25 (d, 1H), 7.2 (s, 1H), 7.08 (dd, 1H), 3.76(m, 1H), 2.88 (m, 2H), 2.55-2.68 (m, 6H), 2.4 (m, 2H), 2.05 (m, 2H),1.78 (m, 2H), 1.5-1.62 (m, 10H).

Example 157 4-(4-Trifluoromethyl-phenyl)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized from compound 194 (see example 156) and4-trifluoromethyl-phenyl boronic acid analogously to the methoddescribed in Example 156.

Yield: 35 mg (20%) of a white crystals; MS (ESI): 513 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.75 (s, 1H), 8.25 (d, 1H), 7.85 (s, 4H), 7.48 (d,1H), 7.32 (s, 1H), 7.28 (dd, 1H), 7.15 (d, 1H), 3.75 (m, 1H), 2.87 (m,2H), 2.5-2.6 (m, 6H), 2.38 (m, 2H), 2.0 (m, 2H), 1.78 (m, 2H), 1.48-1.55(m, 10H).

Example 158 4-p-Tolyl-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]amide

This compound is synthesized from compound 194 (see example 156) and4-p-tolyl boronic acid analogously to the method described in Example156.

Yield: 40 mg (26%) of a white foam; MS (ESI): 459 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.6 (s, 1H), 8.25 (d, 1H), 7.53 (d, 2H), 7.48 (d,1H), 7.32 (d, 2H), 7.3 (s, 1H), 7.2 (dd, 1H), 7.05 (d, 1H), 3.75 (m,1H), 2.5-2.6 (m, 8H), 2.38 (s, 3H), 2.33-2.4 (m, 2H), 2.0 (m, 2H), 1.75(m, 2H), 1.48-1.55 (m, 10H).

Example 159 4-(4-Dimethylamino-phenyl)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized from compound 194 (see example 156) and(4-dimethylamino-phenyl)-boronic acid analogously to the methoddescribed in Example 156.

Yield: 45 mg (28%) of a white foam; MS (ESI): 488.2 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.55 (s, 1H), 8.25 (d, 1H), 7.3-7.4 (m, 2H),7.15-7.25 (m, 3H), 7.07 (m, 2H), 3.8 (s, 3H), 3.78 (s, 3H), 3.75 (m,1H), 2.88 (m, 2H), 2.57 (m, 6H), 2.38 (m, 2H), 2.0 (m, 2H), 1.75 (m,2H), 1.5 (m, 4H), 1.75 (m, 10H).

Example 160 4-Benzo[1,2,5]oxadiazol-5-yl-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized from compound 194 (see example 156) andbenzo[1,2,5]oxadiazol-5-yl-boronic acid analogously to the methoddescribed in Example 156.

Yield: 85 mg (39%) of a white crystals; MS (ESI): 487.1 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.8 (s, 1H), 8.3 (d, 1H), 8.2 (s, 1H), 8.18 (d, 1H),7.95 (d, 1H), 7.52 (m, 1H), 7.38 (s, 1H), 7.3 (d, 1H), 3.75 (m, 1H),2.87 (m, 2H), 2.5-2.6 (m, 6H), 2.36 (m, 2H), 2.0 (m, 2H), 1.75 (m, 2H),1.47-1.58 (m, 10H).

Example 161 4-(4-Methoxy-phenyl)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized from compound 194 (see example 156) and(4-methoxy-phenyl)-boronic acid analogously to the method described inExample 156.

Yield: 22 mg (38%) of a white foam; MS (ESI): 475.4 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.59 (s, 1H), 8.23 (d, 1H), 7.49 (d, 2H), 7.32 (m,2H), 7.18 (dd, 1H), 7.0 (d, 1H), 6.85 (d, 2H), 3.75 (m, 1H), 2.97 (s,6H), 2.87 (m, 2H), 2.56 (m, 6H), 2.48 (m, 2H), 2.0 (m, 2H), 1.77 (m,2H), 1.52 (m, 10H).

Example 162 4-(3-Cyano-phenyl)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized from compound 194 (see example 156) and3-cyano-phenyl boronic acid analogously to the method described inExample 156.

Yield: 115 mg (55%) of a white crystals; MS (ESI): 470.1 [M+H]⁺, 1H-NMR(DMSO-d₆): 5 (ppm) 11.75 (s, 1H), 8.38 (d, 1H), 8.05 (s, 1H), 7.98 (dd,1H), 7.88 (m, 1H), 7.72 (dd, 1H), 7.47 (d, 1H), 7.3 (d, 1H), 7.25 (d,1H), 7.15 (d, 1H), 3.75 (m, 1H), 2.87 (m, 2H), 2.48-2.6 (m, 6H), 2.37(m, 2H), 2.0 (m, 2H), 1.75 (m, 2H), 1.47-1.58 (m, 10H).

Example 163 4-(4-Ethoxy-phenyl)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)piperidin-4-yl]-amide

This compound is synthesized from compound 194 (see example 156) and(4-ethoxy-phenyl)-boronic acid analogously to the method described inExample 156.

Yield: 40 mg (24%) of beige crystals; MS (ESI): 487 [M−H]⁻, 1H-NMR(DMSO-d₆): δ (ppm) 11.6 (s, 1H), 8.25 (d, 1H), 7.57 (d, 2H), 7.38 (d,1H), 7.32 (s, 1H), 7.2 (dd, 1H), 7.05 (d, 2H), 7.02 (d, 1H), 4.07 (q,2H), 3.75 (m, 1H), 2.85 (m, 2H), 2.50-2.58 (m, 6H), 2.38 (m, 2H), 2.0(m, 2H), 1.75 (m, 2H), 1.48-1.58 (m, 8H), 1.38 (t, 3H).

Example 164 4-[3-(3-Methoxy-propoxy)-phenyl]-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized from compound 194 (see example 156) and[3-(3-methoxy-propoxy)-phenyl]-boronic acid analogously to the methoddescribed in Example 156.

Yield: 160 mg (67%) of beige foam; MS (ESI): 533.2 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.65 (s, 1H), 8.28 (d, 1H), 7.38-7.43 (m, 2H), 7.32(s, 1H), 7.2-7.25 (m, 2H), 7.15 (m, 1H), 7.08 (d, 1H), 6.95 (dd, 1H),4.1 (t, 2H), 3.75 (m, 1H), 3.48 (t, 2H), 3.25 (s, 3H), 2.85 (m, 2H),2.48-2.58 (m, 8H), 2.35 (m, 2H), 1.95-2.04 (m, 4H), 1.75 (m, 2H),1.48-1.6 (m, 10H).

Example 165 4-(4-Trifluoromethoxy-phenyl)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized from compound 194 (see example 156) and4-Trifluoromethoxy-phenyl boronic acid analogously to the methoddescribed in Example 156.

Yield: 75 mg (42%) of white foam; MS (ESI): 529 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.7 (s, 1H), 8.28 (d, 1H), 7.78 (d, 2H), 7.50 (d,2H), 7.44 (d, 1H), 7.3 (s, 1H), 7.25 (dd, 1H), 7.08 (d, 1H), 3.75 (m,1H), 2.87 (m, 2H), 2.5-2.6 (m, 6H), 2.38 (m, 2H), 2.0 (m, 2H), 1.75 (m,2H), 1.48-1.6 (m, 10H).

Example 166 4-(2,4-Dimethoxy-phenyl)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized from compound 194 (see example 156) and(2,4-dimethoxy-phenyl)-boronic acid analogously to the method describedin Example 156.

Yield: 120 mg (53%) of a beige foam; MS (ESI): 505.2 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.45 (s, 1H), 8.15 (d, 1H), 7.34 (d, 1H), 7.2 (d,1H), 7.15 (dd, 1H), 6.93 (d, 1H), 6.9 (d, 1H), 6.7 (d, 1H), 6.65 (dd,1H), 3.84 (s, 3H), 3.73 (m, 1H), 3.68 (s, 3H), 2.85 (m, 2H), 2.47-2.58(m, 8H), 2.35 (m, 2H), 1.98 (m, 2H), 1.75 (m, 2H), 1.47-1.58 (m, 8H).

Example 167 4-(3,4-Dimethoxy-phenyl)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized from compound 194 (see example 156) and(3,4-dimethoxy-phenyl)-boronic acid analogously to the method describedin Example 156.

Yield: 65 mg (29%) of white crystals; MS (ESI): 505.2 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.6 (s, 1H), 8.25 (d, 1H), 7.3-7.4 (m, 2H),7.15-7.25 (m, 3H), 7.07 (m, 2H), 3.8 (s, 3H), 3.78 (s, 3H), 3.75 (m,1H), 2.88 (m, 2H), 2.57 (m, 6H), 2.38 (m, 2H), 2.0 (m, 2H), 1.75 (m,2H), 1.5 (m, 4H), 1.75 (m, 10H).

Example 168 4-Benzo[1,3]dioxol-5-yl-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized from compound 194 (see example 156) andbenzo[1,3]dioxol-5-yl-boronic acid analogously to the method describedin Example 156.

Yield: 75 mg (34%) of a white crystals; MS (ESI): 489.1 [M+H]⁺, 1H-NMR(DMSO-d₆): 5 (ppm) 11.6 (s, 1H), 8.28 (d, 1H), 7.38 (d, 1H), 7.3 (m,1H), 7.2 (d, 1H), 7.18 (m, 1H), 7.1 (dd, 1H), 7.04 (dd, 1H), 6.08 (s,2H), 3.75 (m, 1H), 2.87 (m, 2H), 2.48-2.6 (m, 6H), 2.37 (m, 2H), 2.0 (m,2H), 1.75 (m, 2H), 1.47-1.58 (m, 10H).

Example 169 4-Pyridin-4-yl-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)piperidin-4-yl]-amide

This compound is synthesized from compound 194 (see example 156) andpyridin-4-yl-boronic acid analogously to the method described in Example156.

Yield: 35 mg (53%) of beige crystals; MS (ESI): 446.2 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.8 (s, 1H), 8.68 (d, 2H), 8.3 (d, 1H), 7.68 (d,1H), 7.5 (d, 1H), 7.38 (s, 1H), 7.3 (m, 1H), 7.2 (d, 1H), 3.75 (m, 1H),2.88 (m, 2H), 2.45-2.6 (m, 6H), 2.38 (m, 2H), 2.0 (m, 2H), 1.75 (m, 2H),1.48-1.6 (m, 10H).

Example 170 4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized from compound 194 (see example 156) and(6-methoxy-pyridin-3-yl)-boronic acid analogously to the methoddescribed in Example 156.

Yield: 125 mg (59%) of a white crystals; MS (ESI): 476.4 [M+H]⁺, 1H-NMR(DMSO-d₆): 5 (ppm) 11.65 (s, 1H), 8.48 (d, 1H), 8.3 (d, 1H), 7.98 (dd,1H), 7.42 (d, 1H), 7.35 (s, 1H), 7.24 (dd, 1H), 7.08 (d, 1H), 6.97 (d,1H), 3.93 (s, 3H), 3.75 (m, 1H), 2.87 (m, 2H), 2.48-2.6 (m, 6H), 2.35(m, 2H), 2.0 (m, 2H), 1.75 (m, 2H), 1.47-1.58 (m, 10H).

Example 171 4-(4-Ethoxy-phenyl)-1H-indole-2-carboxylic acid[1-(2-piperidin-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized from compound 195 (preparation see below)and (4-ethoxy-phenyl)-boronic acid analogously to the method describedin Example 156.

Yield: 100 mg (46%) of yellow crystals; MS (ESI): 475 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.6 (s, 1H), 8.25 (d, 1H), 7.55 (d, 2H), 7.35 (d,1H), 7.3 (s, 1H), 7.2 (dd, 1H), 7.05 (d, 2H), 7.02 (d, 1H), 4.08 (q,2H), 3.73 (m, 1H), 2.87 (m, 2H), 2.25-2.4 (m, 8H), 2.0 (m, 2H), 1.75 (m,2H), 1.3-1.57 (m, 8H), 1.38 (t, 3H).

(1) 4-Bromo-1H-indole-2-carboxylic acid[1-(2-piperidin-1-yl-ethyl)-piperidin-4-yl]-amide (195)

This compound is synthesized from 4-bromo-1H-indole-2-carboxylic acidand amine 4 analogously to the method described above for the synthesisof 194 (see example 156).

MS (ESI): 433, 435 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.9 (s, 1H), 8.4(d, 1H), 7.4 (d, 1H), 7.23 (d, 1H), 7.19 (s, 1H), 7.08 (dd, 1H), 3.76(m, 1H), 2.88 (m, 2H), 2.3-2.4 (m, 8H), 2.0 (m, 2H), 1.78 (m, 2H),1.3-1.6 (m, 8H).

Example 172 4-(4-Methoxy-phenyl)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized from compound 196 (preparation see below)and (4-methoxy-phenyl)-boronic acid analogously to the method describedin Example 156.

Yield: 55 mg (35%) of white foam; MS (ESI): 477.2 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.6 (s, 1H), 8.25 (d, 1H), 7.58 (d, 2H), 7.36 (d,1H), 7.3 (s, 1H), 7.2 (dd, 1H), 7.05 (d, 2H), 7.02 (d, 1H), 4.55 (br,1H), 3.85 (s, 3H), 3.78 (m, 1H), 3.45 (m, 1H), 2.9 (m, 2H), 2.78 (m,2H), 2.45 (m, 4H), 2.15 (m, 2H), 2.05 (m, 2H), 1.3-1.8 (m, 8H).

(1) 4-Bromo-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide (196)

This compound is synthesized from 4-Bromo-1H-indole-2-carboxylic acidand amine 21 analogously to the method described for 194 (see example156).

MS (ESI): 449, 451.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 11.9 (s, 1H),8.42 (d, 1H), 7.4 (d, 1H), 7.23 (d, 1H), 7.2 (s, 1H), 7.08 (dd, 1H), 3.8(m, 1H), 3.5 (m, 1H), 2.88 (m, 2H), 2.95 (m, 2H), 2.86 (m, 2H), 2.6 (m,2H), 2.52 (m, 2H), 2.3 (m, 2H), 2.12 (m, 2H), 1.8 (m, 2H), 1.75 (m, 2H),1.58 (m, 2H), 1.43 (m, 2H).

Example 173 4-(4-Ethoxy-phenyl)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized from compound 196 (see example 172) and(4-ethoxy-phenyl)-boronic acid analogously to the method described inExample 156.

Yield: 45 mg (21%) of white crystals; MS (ESI): 491 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.6 (s, 1H), 8.24 (d, 1H), 7.54 (d, 2H), 7.34 (d,1H), 7.3 (s, 1H), 7.19 (dd, 1H), 7.06 (d, 2H), 7.0 (d, 1H), 4.47 (d,1H), 4.08 (q, 2H), 3.73 (m, 1H), 3.40 (m, 1H), 2.85 (m, 2H), 2.68 (m,2H), 2.36 (m, 4H), 1.98 (m, 4H), 1.74 (m, 2H), 1.65 (m, 2H), 1.51 (m,2H), 1.37 (t, 3H), 1.32 (m, 2H).

Example 174 4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized from compound 196 (see example 172) and(6-methoxy-pyridin-3-yl)-boronic acid analogously to the methoddescribed in Example 156.

Yield: 28 mg (18%) of white crystals; MS (ESI): 478.1 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.68 (s, 1H), 8.47 (d, 1H), 8.27 (d, 1H), 7.95 (dd,1H), 7.40 (d, 1H), 7.35 (s, 1H), 7.23 (dd, 1H), 7.09 (d, 1H), 6.97 (d,1H), 4.48 (d, 1H), 3.92 (s, 3H), 3.75 (m, 1H), 3.39 (m, 1H), 2.85 (m,2H), 2.68 (m, 2H), 2.36 (m, 4H), 1.99 (m, 4H), 1.75 (m, 2H), 1.65 (m,2H), 1.54 (m, 2H), 1.35 (m, 2H).

Example 175 4-(4-Methoxy-phenyl)-1H-indole-2-carboxylic acid{1-[2-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized from compound 197 (preparation see below)and (4-methoxy-phenyl)-boronic acid analogously to the method describedin Example 156.

Yield: 90 mg (57%) of white foam; MS (ESI): 503.2 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.6 (s, 1H), 8.25 (d, 1H), 7.55 (d, 2H), 7.35 (d,1H), 7.3 (m, 1H), 7.2 (dd, 1H), 7.05 (d, 2H), 7.02 (d, 1H), 4.25 (br s,1H), 3.82 (s, 3H), 3.78 (m, 1H), 3.75 (m, 1H), 3.1 (m, 2H), 2.88 (m,2H), 2.38 (m, 4H), 2.0 (m, 4H), 1.85 (m, 2H), 1.77 (m, 4H), 1.55 (m,4H).

(1) 4-Bromo-1H-indole-2-carboxylic acid{1-[2-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-ethyl]-piperidin-4-yl}-amide(197)

This compound is synthesized from 4-Bromo-1H-indole-2-carboxylic acidand amine 24 analogously to the method described for 194 (see example156).

MS (ESI): 475.3, 477 [M+H]⁺, 1H-NMR (DMSO-d₆, 150° C.): δ (ppm) 11.7 (brs, 1H), 8.28 (br s, 1H), 7.49 (d, 1H), 7.25 (d, 1H), 7.15 (s, 1H), 7.1(dd, 1H), 4.1 (br s, 1H), 3.97 (m, 3H), 3.5 (m, 2H), 3.0 (m, 2H), 2.5(m, 6H), 1.9-2.2 (m, 10H).

Example 176 4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acid{1-[2-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-ethyl]-piperidin-4-yl}-amide

This compound is synthesized from compound 197 (see example 175) and(6-methoxy-pyridin-3-yl)-boronic acid analogously to the methoddescribed in Example 156.

Yield: 90 mg (57%) of white foam; MS (ESI): 504.2 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 11.6 (s, 1H), 8.48 (d, 1H), 8.28 (d, 1H), 7.97 (dd,1H), 7.4 (d, 1H), 7.35 (m, 1H), 7.23 (dd, 1H), 7.08 (d, 1H), 6.95 (d,1H), 4.23 (br, 1H), 3.93 (s, 3H), 3.78 (m, 1H), 3.75 (m, 1H), 3.1 (m,2H), 2.88 (m, 2H), 2.38 (m, 4H), 2.0 (m, 4H), 1.8 (m, 6H), 1.53 (m, 4H).

Alternatively, the 4-alkoxy-indole-2-Carboxamides are Prepared as Shownin Reaction Scheme 22.

Reaction Scheme 22:

Example 177 4-Hydroxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)piperidin-4-yl]-amide

The methoxy derivative from example 1 (100 mg, 0.25 mmol) is dissolvedin 5 ml of DCM. A solution of BBr3 (1M in DCM, 2.5 ml, 2.5 mmol) isadded and the mixture is stirred for 18 hours. It is then poured ontoice and washed with EtOAc (30 ml). The pH of the water layer is adjustedto 9 and extracted twice with EtOAc. The organic layers are combinedwashed with brine, dried over anhydrous sodium sulfate and evaporated.

Yield: 24 mg (25%).

MS (ESI): 385.3 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 9.62 (s, 1H), 8.14 (d,1H), 7.2 (d, 1H), 6.94 (t, 1H), 6.86 (d, 1H), 6.37 (d, 1H), 3.75 (m,1H), 2.89 (m, 2H), 2.53-2.65 (m, 6H), 2.39 (m, 2H), 2.03 (m, 2H), 1.78(m, 2H), 1.47-1.68 (m, 10H), 1.25 (m, 1H).

Synthesis of the benzthiophene-2-carboxamides

The 4-alkoxy-benzthiophene-2-Carboxylates are Synthesized Starting from4-thiophen-2-yl-butyric Acid (Reaction Scheme 23).

Reaction Scheme 2312:

(1) 6,7-Dihydro-5H-benzo[b]thiophen-4-one (198)

Ortho-phosphoric acid (85%, 0.27 ml, 3.7 mmol) is dissolved in aceticacid anhydride (13 ml) and after addition of 4-thiophen-2-yl-butyricacid (9 g, 52.9 mmol) the mixture is stirred at 120° C. for 2.5 h. Thebrown solution is cooled down using an ice bath, water is added and thereaction mixture is extracted with dichloromethane. The organic layersare washed with 2M NaOH solution and twice with water until a neutral pHis reached. The solution is dried over Na2SO4 and evaporated underreduced pressure. The crude product is obtained as a brown oil (7.84 g),which is further purified by flash-chromatography (silica gel, ethylacetate/hexane 9:1).

Yield: 5.83 g (72%) of a slightly yellow solid. MS (ESI): 152 [M]⁺,1H-NMR (DMSO-d₆): δ (ppm) 7.38 (d, 1H), 7.25 (d, 1H), 3.03 (t, 2H), 2.48(m, 2H), 2.12 (t, 2H).

(2) 5-Bromo-6,7-dihydro-5H-benzo[b]thiophen-4-one (199)

6,7-Dihydro-5H-benzo[b]thiophen-4-one (198, 5.8 g, 38.3 mmol) isdissolved in 200 ml of dry diethyl ether and cooled down to −10° C. Asolution of bromine (6.1 g, 38.3 mmol) in 30 ml of tetrachloromethaneand 2-3 drops of diethyl ether is slowly added. The mixture is stirredfor 15 min at −10° C., 15 min at 0° C. and 18 h at room temperature.Then water and diethyl ether is added slowly. The organic layers arewashed with water, dried over Na2SO4 and evaporated.

Yield: 8.7 g of a yellow solid (containing 23% of starting material). MS(ESI): 230, 232 [M]⁺,

1H-NMR (DMSO-d₆): δ (ppm) 7.46 (d, 1H), 7.3 (d, 1H), 4.87 (dt, 1H), 3.1(m, 2H), 2.45 (m, 2H).

(3) Benzo[b]thiophen-4-ol (200)

5-Bromo-6,7-dihydro-5H-benzo[b]thiophen-4-one (199, 77% pure, 8.7 g,28.9 mmol), LiBr (5.7 g, 65.1 mmol) and Li2CO3 (4.3 g, 57.8 mmol) areplaced under argon in 300 ml of DMF and refluxed for 3 h. The reactionmixture is allowed to cool down to room temperature and evaporated underhigh vacuum. After addition of ice water and cold 2M aqueous HClsolution the mixture is extracted with diethyl ether. The organic layersare extracted with 2M NaOH and the combined aqueous layers are acidifiedwith concentrated HCl. The product is extracted twice with ethyl acetateand the organic layers are washed with saturated NaCl solution, driedover Na2SO4 and evaporated under reduced pressure.

Yield: 4.7 g of a brown solid, which is used without furtherpurification. MS (ESI): 149.0 [M−H]⁻, 1H-NMR (DMSO-d₆): δ (ppm) 9.95 (brs, 1H), 7.55 (d, 1H), 7.45 (d, 1H), 7.38 (d, 1H), 7.15 (dd, 1H), 6.72(d, 1H).

(4) 4-Isobutoxy-benzo[b]thiophene (201)

Benzo[b]thiophen-4-ol (200, 4.3 g, 28.9 mmol) and iso-butanol (3.2 ml,34.7 mmol) are dissolved under argon in 150 ml of toluene. Afteraddition of triphenylphosphine (9.1 g, 34.7 mmol) and a 40% solution ofDEAD in toluene (16.8 ml, 34.7 mmol), the mixture is stirred at 120° C.over night. After cooling down, the reaction mixture is subsequentlywashed with saturated aqueous NaHCO3 solution and NaCl solution, driedover Na2SO4 and evaporated under reduced pressure. Triphenylphosphinoxidis removed by crystallization from ethyl acetate and hexane and thecrude product is further purified by flash chromatography (silica gel,hexane/ethyl acetate 9:1).

Yield: 5.4 g (91%) of a yellow oil. MS (ESI): 206 [M]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 7.62 (d, 1H), 7.5 (d, 1H), 7.44 (d, 1H), 7.27 (dd,1H), 6.85 (d, 1H), 3.88 (d, 2H), 2.12 (m, 1H), 1.05 (d, 6H).

(5) 4-Isobutoxy-benzo[b]thiophene-2-carboxylic acid (202)

A 1.6 M solution of n-butyl lithium in hexane (18 ml, 28.8 mmol) isdissolved under an argon atmosphere in 100 ml of dry diethyl ether,followed by dropwise addition of a solution of4-Isobutoxy-benzo[b]thiophene (201, 5.4 g, 26.1 mmol) in 40 ml ofdiethyl ether. The reaction mixture is refluxed for 45 min, then cooleddown and transferred via syringe to a mixture of excess dry ice (115 g,2.61 mol) in diethyl ether (the dry ice is washed before twice withdiethyl ether). The mixture is allowed to stir overnight at roomtemperature, then distributed between diethyl ether and water. The etherlayers are reextracted with water. The aqueous layers are acidified with2M aqueous HCl solution, and the precipitate is filtered off, washedwith water and dried under high vacuum.

Yield: 3.72 g (57%) of a white solid. MS (ESI): 250 [M]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 13.4 (br s, 1H), 7.98 (s, 1H), 7.55 (d, 1H), 7.43(dd, 1H), 6.9 (d, 1H), 3.9 (d, 2H), 2.14 (m, 1H), 1.05 (d, 6H).

Example 178 4-Methoxy-benzo[b]thiophene-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]amide

A solution of a mixture of 4- and6-methoxy-benzo[b]thiophene-2-carboxylic acid (C. R. Hebd. Seances Acad.Sci. 1965, 261, 705) (440 mg, 1.05 mmol), amine 5 (357 mg, 1.051) in 10ml of DMF is treated with EDC (178 mg, 1.05 mmol), HOBT hydrate (178 mg,1.15 mmol) and triethylamine (0.44 ml, 3.15 mmol). The mixture isstirred over night and then evaporated under high vacuum. The cruderesidue is dissolved in ethyl acetate and washed twice with sodiumbicarbonate (10%), brine and dried over sodium sulfate. The crudeproduct is then purified by flash chromatography (ethylacetate/methanol/ammonia 90:10:1).

Yield: 45 mg (10%) of a yellow solid (and 84 mg of the 6-substitutedisomer). MS (ESI): 416.1 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 8.53 (d, 1H),8.2 (s, 1H), 7.5 (d, 1H), 7.37 (dd, 1H), 6.9 (d, 1H), 3.94 (s, 3H), 3.7(br m, 1H), 2.88 (m, 2H), 2.6 (m, 6H), 2.4 (m, 2H), 2.0 (m, 2H), 1.75(m, 2H), 1.47-1.6 (m, 10H).

Example 179 4-Isobutoxy-benzo[b]thiophene-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized from compound 202 and amine 5 analogouslyto the method described in Example 178.

Yield: 340 mg (53%) of beige powder. MS (ESI): 458.4 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 8.58 (d, 1H), 8.15 (s, 1H), 7.5 (d, 1H), 7.35 (dd,1H), 6.88 (d, 1H), 3.9 (d, 2H), 3.7 (br m, 1H), 2.9 (m, 2H), 2.6 (m,6H), 2.4 (m, 2H), 2.15 (m, 1H), 2.0 (m, 2H), 1.78 (m, 2H), 1.5-1.65 (m,10H), 1.05 (d, 6H).

Example 180 4-Isobutoxy-benzo[b]thiophene-2-carboxylic acid[1-(2-piperidin-1-yl-ethyl)-piperidin-4-yl]-amide

This compound is synthesized from compound 202 and amine 1 analogouslyto the method described in Example 178.

Yield: 93 mg (26%) of beige powder. MS (ESI): 444.3 [M+H]⁺, 1H-NMR(DMSO-d₆): δ (ppm) 8.58 (d, 1H), 8.15 (s, 1H), 7.48 (d, 1H), 7.35 (dd,1H), 6.88 (d, 1H), 3.9 (d, 2H), 3.7 (br m, 1H), 2.88 (m, 2H), 2.3-2.4(m, 8H), 2.15 (m, 1H), 1.98 (m, 2H), 1.78 (m, 2H), 1.58 (m, 2H), 1.47(m, 4H), 1.35 (m, 2H), 1.05 (d, 6H).

Synthesis of the benzofuran-2-carboxamides Example 1814-Methoxy-benzofuran-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)piperidin-4-yl]-amide

This compound is synthesized analogously to Example 1 from4-Methoxy-benzofuran-2-carboxylic acid and amine 5.

MS (ESI): 400.2 [M+H]⁺, 1H-NMR (DMSO-d₆): δ (ppm) 8.42 (d, 1H), 7.5 (s,1H), 7.37 (t, 1H), 7.21 (d, 1H), 6.84 (d, 1H), 3.92 (s, 3H), 3.72 (m,1H), 2.88 (m, 2H), 2.35-2.68 (m, 8H), 2.02 (m, 2H), 1.76 (m, 2H),1.48-1.67 (m, 10H).

The compounds of formula I in free form or in pharmaceuticallyacceptable salt form exhibit valuable pharmacological properties, e.g.as CCR2 and CCR5 antagonists as indicated in in vitro tests as describedbelow.

a) CCR2 Membrane Binding Assay

The SPA (Scintillation Proximity Assay) technology is used to show thatthe test compounds prevent MCP-1 from binding to cell membranesexpressing the CCR2 receptor. Transfected CHO-dukX cells stablyexpressing the hCCR2b gene are grown in MEM alpha medium to a confluencyof between 70 and 80%. After discarding the medium, 30 ml ice-coldphysiological buffer solution containing 1 mM EDTA are added and thecells removed from the plate using a scraper. The cell suspension iscentrifuged at 800 g for 10′ at 4° C. and the cell pellet resuspended inbuffer. Cell lysis is done using a Polytron PTI300D instrument at 28 000RPM for 2 times 30 seconds on ice. Membranes are collected bycentrifugation at 42 000 g for 20 minutes at 4° C. and subjected to asecond round of lysis (Polytron, 28 000 RPM, 2×30 seconds on ice).Following centrifugation at 42 000 g for 20 minutes at 4° C. themembranes are resuspended in buffer at a protein concentration of 2mg/ml and stored at −80° C. Ten millimolar stock solutions of testcompounds in 100% DMSO are prepared. Test compounds are further dilutedin buffer to yield the four-fold concentrated solutions for the teststhat assayed a range of 10⁻¹⁰ to 10⁻⁵ M. The SPA assay is performed in afinal volume of 200 μl per well in 96 well plates. The components areadded per well in the following order:

50 μl Buffer (+/− test compound) 50 μl Wheat germ agglutinin-SPA beads(1.25 mg/well) in buffer 50 μl CCR2B membrane suspension diluted withbuffer to 0.04 mg/ml (2 μg/well), alternatively 50′000 cells per well 50μl [¹²⁵I] MCP-1 in buffer (60 pM final concentration, 2.5 μCi/plate)

After addition of all components the plate is sealed and incubated for90 minutes at room temperature with constant shaking. Followingincubation the plate is centrifuged at 1000 RPM in a Sorvall RC3Bcentrifuge for 4 minutes at room temperature and counted for 3 minutesper well in a TOP COUNT instrument (Packard). The quench-correctedcounts are used for the analysis of radioligand binding.

Compounds of formula I have an IC₅₀ between 0.0003 and 10 μM.

In a similar manner, binding assays for the rat, mouse and rhesus monkeyCCR2 receptors have been established. Due to the species specificity ofthe CCR2 antagonists, the compounds of formula I have an IC₅₀ between0.015 and 10 μM on mouse CCR2 and between 0.020 and 10 μM on rat CCR2.

b) CCR2 Functional Assay —Ca2+ Mobilization

hCCR2b-CHO#84 Cells:

CHOdukX cell line stably expressing the hCCR2 gene is grown in MEMα upto a confluence of 80%. The day before the experiment, cells areharvested from the tissue culture flask by trypsinization, washed,plated in a black/clear bottom 96-well plate at 5×10⁴ cells per well andcultured overnight at 37° C. in a humid atmosphere enriched with 5% CO₂.On the next day, cells are washed twice and loaded for 1 hour at RT inthe dark with 2 μM Fluo-4 in buffer C. After two further washes, thecells are resuspended in buffer D. Serial dilutions of the compounds, inbuffer D, are mixed with the cells and incubated for half an hour at RTin the dark. Cells are then stimulated by the injection of MCP-1 andcalcium fluxes are monitored using the Flexstation™, a benchtop scanningfluorometer with and integrated fluid transfer workstation.

20 mM 625 μM HBSS* 1X Hepes 0.1% BSA Probenecid 0.5% BSA Buffer A X XBuffer B X X X Buffer C X X X Buffer D X X X X *Hank's balanced altSolution (10X) without phenol red (#14065-049, Gibco BRL).hCCR2b-300.19 cells:

Pre-B cell line 300-19 stably expressing the hCCR2 gene (Loetscher etal., J. Biol. Chem. 276 (S), 2986-91 (2001)) is grown in RPMI 1640 withglutamax-I supplemented with 1×MEM non essential amino-acid, 1 mM sodiumpyruvate, 5×10⁻⁵ M β-mercaptoethanol and 10% FCS. For the experiment,the cells are used in the exponential growing phase, at a maximalconcentration of 1.5×10⁶ cells per ml. Cells are washed in buffer A andloaded at about 2.10⁶ cells per ml in 2 μM fluo-4 in buffer B for 30min. in the dark, at 37° C. in a waterbath. After two washes with bufferA, cells are plated in black/clear bottom 96-well plate at 2×10⁵ cellsper well in buffer B. All following steps, including the compound andthe chemokine dilutions, are performed as described above for thehCCR2b-CHO#84 cells, except that buffer B is used instead of buffer D.

In this assay, compounds of formula I have an IC₅₀ between 0.0005 and 10μM.

c) CCR2 Functional Assay—Chemotaxis

An in vitro cell migration assay for CCR2-dependent chemotaxis based onTranswell™ membrane inserts is used to profile the compounds. The assayis performed with the human monocytic THP-1 cell line and activatedperipheral blood lymphocytes (PBL). THP-1 cells are cultured in RPMI1640supplemented with 10% heat-inactivated FCS. Activated PBL are preparedfrom human blood by elutriation and then activated by culture onanti-human CD3-coated culture plates and expanded by subsequent culturein medium supplemented with IL-2. Aliquots of activated PBL are frozenin liquid nitrogen and used in migration experiments after thawing andovernight culture. Cells from cultures at a density of less than 1.2×10⁶cells/ml are counted, washed and resuspended at an appropriate densityin RPMI1640 containing 0.5% BSA. Transwell™ membrane inserts of 6.5 mmdiameter, 3 or 8 μm pore size and tissue culture treated polycarbonatemembrane are used for the migration assays. The transwell inserts areloaded with cells and compounds in a final volume of 100 μl inRPMI1640/0.5% BSA. For THP-1 cells, 8 μm pore size inserts are used. ForPBLs the use of 3 μm pore size inserts resulted in lower non-specificcounts. The inserts are placed in a 24-well tissue culture platecontaining recombinant human MCP-1 and compounds in a final volume of600 μl. After allowing the cells to migrate to the bottom compartment,the assay is stopped by removing and discarding the transwell inserts.Cells in the bottom compartment are collected and counted on a FACScanflow cytometer by acquiring all events for 30 s with settingsestablished for each cell type. Migration is expressed as absolute cellcounts/30 s relative to the input cell number measured under the sameconditions.

In this assay, compounds of formula I have an IC₅₀ between 0.0012 and 10μM.

d) CCR5 Membrane Binding Assay

Human CCR5 is used to generate stable transfectants in CHO K1 cells.Membranes prepared from these CCR5 transfectants are used in aradioligand binding assay using 125-I-MIP-1α as a ligand and thecompounds of formula I are tested for inhibitory activity. The data arereported as IC₅₀, i.e. the concentration of compound required to achieve50% inhibition of [I-125]MIP-1α binding. In this assay, compounds offormula I have an IC₅₀ between 0.004 and 10 μM.

The Agents of the invention are effective as dual CCR-2 and CCR-5antagonists. Thus the Agents of the invention are useful for theprophylaxis and treatment of CCR-2 and CCR-5 mediated diseases ormedical conditions. CCR-2 and CCR-5 play an important role in leukocytetrafficking, in particular in monocyte migration to inflammatory sitesand thus the agents of the invention may be used to inhibit monocytemigration e.g. in the treatment of inflammatory conditions, allergiesand allergic conditions, autoimmune diseases, chronic pain, graftrejection, cancers which involve leukocyte filtration, stenosis orrestenosis, atherosclerosis, rheumatoid arthritis, osteoarthritis andchronic pain.

Diseases or conditions which may be treated with the Agents of theInvention include:

Inflammatory or allergic conditions, including respiratory allergicdiseases such as asthma, allergic rhinitis, COPD, hypersensitivity lungdiseases, hypersensitivity pneumonitis, interstitial lung disease (ILD),(e.g. idiopathic pulmonary fibrosis, or ILD associated with autoimmunediseases such as RA, SLE, etc.); chronic obstructive pulmonary disease,anaphylaxis or hypersensitivity responses, drug allergies (e.g. topenicillins or cephalosporins), and insect sting allergies; inflammatorybowel diseases, such as Crohn's disease and ulcerative colitis;spondyloarthropathies, sclerodoma; psoriasis and inflammatory dermatosessuch as dermatitis, eczema, atopic dermatitis, allergic contactdermatitis, urticaria; vasculitis;

Autoimmune diseases, in particular autoimmune diseases with an aetiologyincluding an inflammatory component such as arthritis (for examplerheumatoid arthritis, arthritis chronica progrediente, psoriaticarthritis and arthritis deformans) and rheumatic diseases, includinginflammatory conditions and rheumatic diseases involving bone loss,inflammatory pain, hypersensitivity (including both airwayshypersensitivity and dermal hypersensitivity) and allergies. Specificauto-immune diseases for which Antibodies of the Invention may beemployed include autoimmune haematological disorders (including e.g.hemolytic anaemia, aplastic anaemia, pure red cell anaemia andidiopathic thrombocytopenia), systemic lupus erythematosus,polychondritis, sclerodoma, Wegener granulomatosis, dermatomyositis,chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnsonsyndrome, idiopathic sprue, autoimmune inflammatory bowel disease(including e.g. ulcerative colitis, Crohn's disease and Irritable BowelSyndrome), autoimmune thyroiditis, Behcet's disease, endocrineopthalmopathy, Graves disease, sarcoidosis, multiple sclerosis, primarybiliary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis(anterior and posterior), keratoconjunctivitis sicca and vernalkeratoconjunctivitis, interstitial lung fibrosis, and glomerulonephritis(with and without nephrotic syndrome, e.g. including idiopathicnephrotic syndrome or minimal change nephropathy);

graft rejection (e.g. in transplantation including heart, lung, combinedheart-lung, liver, kidney, pancreatic, skin, or corneal transplants)including allograft rejection or xenograft rejection orgraft-versus-host disease, and organ transplant associatedarteriosclerosis; atherosclerosis;

cancer with leukocyte infiltration of the skin or organs; breast cancer;stenosis or restenosis of the vasculature, particularly of the arteries,e.g. the coronary artery, including stenosis or restenosis which resultsfrom vascular intervention, as well as neointimal hyperplasia;

stroke;

and other diseases or conditions involving inflammatory responsesincluding reperfusion injury, hematologic malignancies, cytokine inducedtoxicity (e.g. septic shock or endotoxic shock), polymyositis,dermatomyositis, and granulomatous diseases including sarcoidosis;infectious diseases, including HIV and AIDS.

The term “treatment” as used herein is to be understood as includingboth therapeutic and prophylactic modes of therapy e.g. in relation tothe treatment of neoplasia, therapy to prevent the onset of clinicallyor preclinically evident neoplasia, or for the prevention of initiationof malignant cells or to arrest or reverse the progression ofpremalignant to malignant cells, as well as the prevention or inhibitionof neoplasia growth or metastasis. In this context, the presentinvention is, in particular, to be understood as embracing the use ofcompounds of the present invention to inhibit or prevent development ofskin cancer, e.g. squamus or basal cell carcinoma consequential to UVlight exposure, e.g. resultant from chronic exposure to the sun.

Agents of the Invention are particularly useful for treating diseases ofbone and cartilage metabolism including osteoarthritis, osteoporosis andother inflammatory arthritides, e.g. rheumatoid arthritis, and bone lossin general, including age-related bone loss, and in particularperiodontal disease.

The Agents of the Invention may also be used in ocular applicationswhich include the treatment of ocular disorders, in particular of ocularinflammatory disorders, of ocular pain including pain associated withocular surgery such as PRK or cataract surgery, of ocular allergy, ofphotophobia of various etiology, of elevated intraocular pressure (inglaucoma) by inhibiting the production of trabecular meshwork inducibleglucocorticoid response (TIGR) protein, and of dry eye disease.

For the above indications, the appropriate dosage will, of course, varydepending upon, for example, the particular Agent of the Invention to beemployed, the subject to be treated, the mode of administration and thenature and severity of the condition being treated. However, inprophylactic use, satisfactory results are generally indicated to beobtained at dosages from about 0.05 mg to about 10 mg per kilogram bodyweight, more usually from about 0.1 mg to about 5 mg per kilogram bodyweight. The frequency of dosing for prophylactic use will normally be inthe range from about once per week up to about once every 3 months, moreusually in the range from about once every 2 weeks up to about onceevery 10 weeks, e.g. once every 4 or 8 weeks. Agent of the Invention isconveniently administered parenterally, intravenously, e.g. into theantecubital or other peripheral vein, intramuscularly, orsubcutaneously. For example, a prophylactic treatment typicallycomprises administering the Agent of the Invention once per month toonce every 2 to 3 months, or less frequently.

The Agents of the invention may be administered in combination withanother active agent. Suitable active agents include antimetabolites(e.g. methotrexate), anti-TNF agents (e.g. Remicade® (infliximab),Enbrel® (Etanercept), Humira® (adalumimab)), anti-IL-1 agents (e.g.pralnacasan, ACZ885), nucleoside and non-nucleoside revers transcriptaseinhibitors, HIV protease inhibitors, fusion inhibitors and otherantiretroviral agents. The active agent or agents may be administeredsimultaneously, separately or sequentially with the Agent of theinvention.

Pharmaceutical compositions of the invention may be manufactured inconventional manner. A composition according to the invention ispreferably provided in lyophilized form. For immediate administration itis dissolved in a suitable aqueous carrier, for example sterile waterfor injection or sterile buffered physiological saline. If it isconsidered desirable to make up a solution of larger volume foradministration by infusion rather as a bolus injection, it isadvantageous to incorporate human serum albumin or the patient's ownheparinised blood into the saline at the time of formulation. Thepresence of an excess of such physiologically inert protein preventsloss of antibody by adsorption onto the walls of the container andtubing used with the infusion solution. If albumin is used, a suitableconcentration is from 0.5 to 4.5% by weight of the saline solution.

The Agents of the Invention may be administered by any conventionalroute, e.g. orally, for example in the form of solutions for drinking,tablets or capsules or parenterally, for example in the form ofinjectable solutions or suspensions. Normally for systemicadministration oral dosage forms are preferred, although for someindications the Agents of the Invention may also be administeredtopically or dermally, e.g. in the form of a dermal cream or gel or likepreparation or, for the purposes of application to the eye, in the formof an ocular cream, gel or eye-drop preparation; or may be administeredby inhalation, e.g., for treating asthma. Suitable unit dosage forms fororal administration comprise e.g. from 25 to 250 mg of Agent of theInvention per unit dosage.

1. A compound of formula (I), or a pharmaceutically acceptable salt,ester or prodrug thereof:

Wherein: Z is CR₁R₂, NR₃, O or S; R is selected from the groupconsisting of hydroxy, an optionally substituted C₁-C₇ alkoxy, C₂-C₇alkenoxy, cycloalkyloxy, aryloxy, heteroaryloxy, aryl-C₁-C₇ alkoxy orheteroaryl-C₁-C₇ alkoxy, an optionally substituted C₁-C₇ alkyl or C₂-C₇alkenyl, an optionally substituted aryl, heteroaryl or an optionallysubstituted aryl-C₁-C₇ alkyl group; R9 represents one or more ringsubstituents selected from the group consisting of H, hydroxy, anoptionally substituted C₁-C₇ alkoxy, C₂-C₇ alkenoxy, cycloalkyloxy,aryloxy, heteroaryloxy, aryl-C₁-C₇ alkoxy or heteroaryl-C₁-C₇ alkoxy, anoptionally substituted C₁-C₇ alkyl or C₂-C₇ alkenyl, an optionallysubstituted aryl, heteroaryl or an optionally substituted aryl-C₁-C₇alkyl group; R₁, R₂, and R₃ are independently selected from the groupconsisting of H and C₁-C₇ alkyl; X is a C₃-C₁₈ cycloalkyl,heterocycloalkyl, aryl or heteroaryl each of which may be optionallysubstituted; Q is a linker of between 1 and 3 atoms in length; Y isC₃-C₁₈ cycloalkyl, heterocycloalkyl, bridged cycloalkyl, bridgedheterocyloalkyl, aryl, heteroaryl, fused aryl-heterocycloalkyl, all ofwhich are independently optionally substituted once or more; theoptional substituent or substituents on R and R9 being independentlyselected from the group consisting of halogen, hydroxy, C₁-C₇ alkyl,mono or di-C₁-C₇ alkylamino, aminocarbonyl, mono or di-C₁-C₇alkylaminocarbonyl, amino, carboxy, C₁-C₇ alkoxy, C₃-C₁₂ cycloalkyl,C₃-C₁₈ heterocycloalkyl, C₁-C₇ alkylcarbonyl, C₁-C₇ alkoxycarbonyl,nitryl, aryl; all of which, except halogen, are independently optionallysubstituted by one or more substituents, selected from the groupconsisting of halogen, hydroxyl, C₁-C₇ alkyl, mono or di-C₁-C₇alkylamino, aminocarbonyl, mono or di-C₁-C₇ alkylaminocarbonyl, amino,carboxy, C₁-C₇ alkoxy, C₃-C₁₂ cycloalkyl, C₃-C₁₈ heterocycloalkyl, C₁-C₇alkylcarbonyl, C₁-C₇ alkoxycarbonyl, nitryl, aryl; the optionalsubstituent or substituents on X being independently selected from thegroup consisting of halogen, hydroxyl, C₁-C₇ alkyl, mono or di-C₁-C₇alkylamino, aminocarbonyl, mono or di-C₁-C₇ alkylaminocarbonyl, amino,carboxy, C₁-C₇ alkoxy, C₃-C₁₂ cycloalkyl, C₃-C₁₈ heterocycloalkyl, C₁-C₇alkylcarbonyl, C₁-C₇ alkoxycarbonyl, nitryl, aryl; all of which, excepthalogen, are independently optionally substituted by one or moresubstituents, selected from the group consisting of halogen, hydroxyl,C₁-C₇ alkyl, mono or di-C₁-C₇ alkylamino, aminocarbonyl, mono ordi-lower alkylaminocarbonyl, amino, carboxy, C₁-C₇ alkoxy, C₃-C₁₂cycloalkyl, C₃-C₁₈ heterocycloalkyl, C₁-C₇ alkylcarbonyl, C₁-C₇alkoxycarbonyl, nitryl, aryl; the optional substituent or substituentson Y being independently selected from the group consisting of halogen,hydroxyl, C₁-C₇ alkyl, mono or di-C₁-C₇ alkylamino, aminocarbonyl, monoor di-C₁-C₇ alkylaminocarbonyl, amino, carboxy, C₁-C₇ alkoxy, C₃-C₁₂cycloalkyl, C₃-C₁₈ heterocycloalkyl, C₁-C₇ alkylcarbonyl, C₁-C₇alkoxycarbonyl, nitryl, aryl; all of which, except halogen, areindependently optionally substituted by one or more substituents,selected from the group consisting of halogen, hydroxyl, C₁-C₇ alkyl,mono or di-C₁-C₇ alkylamino, aminocarbonyl, mono or di-C₁-C₇alkylaminocarbonyl, amino, carboxy, C₁-C₇ alkoxy, C₃-C₁₂ cycloalkyl,C₃-C₁₈ heterocycloalkyl, C₁-C₇ alkylcarbonyl, C₁-C₇ alkoxycarbonyl,nitryl, aryl.
 2. A compound of formula (II), or a pharmaceuticallyacceptable salt, ester or prodrug thereof:

wherein: Z′ is NH, NCH₃, CH₂, S or 0; R′ is hydroxy, an optionallysubstituted C₁-C₇ alkoxy, C₂-C₇ alkenyloxy, cycloalkyl-C₁-C₇ alkyloxy,aryloxy, heteroaryloxy, heteroaryl-C₁-C₇ alkyloxy or aryl-C₁-C₇alkyloxy, an optionally substituted aryl, heteroaryl or an optionallysubstituted aryl-C₁-C₇ alkyl group; X′ is selected from the groupconsisting of:

Q′ is selected from the group consisting of: —CH₂—, —CH₂—CH₂—,—CH₂—CH₂—CH₂—, —CH(CH₃)—CH₂—, —CH₂—CH(CH₃)—, —CH(CH₃)—NH—, —CH₂—N(CH₃)—,—CH₂—CH(CH₂OH)— or —CH(CH₃)—NH(CH₃)—; Y′ is selected from the groupconsisting of: C₃-C₁₈ cycloalkyl, heterocycloalkyl, bridged cycloalkyl,bridged heterocyloalkyl, aryl, heteroaryl, fused aryl-heterocycloalkyl,all of which are independently optionally substituted once or more; theoptional substituent or substituents on R′ being independently selectedfrom the group consisting of halogen, hydroxy, C₁-C₇ alkyl, mono ordi-C₁-C₇ alkylamino, aminocarbonyl, mono or di-C₁-C₇ alkylaminocarbonyl,amino, carboxy, C₁-C₇ alkoxy, C₃-C₁₂ cycloalkyl, C₃-C₁₈heterocycloalkyl, C₁-C₇ alkylcarbonyl, C₁-C₇ alkoxycarbonyl, nitryl,aryl; all of which, except halogen, are independently optionallysubstituted by one or more substituents, selected from the groupconsisting of halogen, hydroxyl, C₁-C₇ alkyl, mono or di-C₁-C₇alkylamino, aminocarbonyl, mono or di-lower alkylaminocarbonyl, amino,carboxy, C₁-C₇ alkoxy, C₃-C₁₂ cycloalkyl, C₃-C₁₈ heterocycloalkyl, C₁-C₇alkylcarbonyl, C₁-C₇ alkoxycarbonyl, nitryl, aryl; the optionalsubstituent or substituents on Y′ being independently selected from thegroup consisting of halogen, hydroxyl, C₁-C₇ alkyl, mono or di-C₁-C₇alkylamino, aminocarbonyl, mono or di-C₁-C₇ alkylaminocarbonyl, amino,carboxy, C₁-C₇ alkoxy, C₃-C₁₂ cycloalkyl, C₃-C₁₈ heterocycloalkyl, C₁-C₇alkylcarbonyl, C₁-C₇ alkoxycarbonyl, nitryl, aryl; all of which, excepthalogen, are independently optionally substituted by one or moresubstituents, selected from the group consisting of halogen, hydroxyl,C₁-C₇ alkyl, mono or di-C₁-C₇ alkylamino, aminocarbonyl, mono ordi-C₁-C₇ alkylaminocarbonyl, amino, carboxy, C₁-C₇ alkoxy, C₃-C₁₂cycloalkyl, C₃-C₁₈ heterocycloalkyl, C₁-C₇ alkylcarbonyl, C₁-C₇alkoxycarbonyl, nitryl, aryl.
 3. A compound according to claim 1selected from: 4-Methoxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]amide4-Isopropoxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide4-Isopropoxy-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-Cyclopropylmethoxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide4-Cyclopropylmethoxy-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-Cyclopropylmethoxy-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-Cyclopropylmethoxy-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-Isobutoxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]amide4-Isobutoxy-1H-indole-2-carboxylic acid[1-(2-piperidin-1-yl-ethyl)piperidin-4-yl]amide4-Isobutoxy-1H-indole-2-carboxylic acid{1-[2-(RS)-2-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-Isobutoxy-1H-indole-2-carboxylic acid{1-[2-(4-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-Isobutoxy-1H-indole-2-carboxylic acid{1-[2-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-Isobutoxy-1H-indole-2-carboxylic acid{1-[2-((R)-3-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-Isobutoxy-1H-indole-2-carboxylic acid{1-[2-((S)-3-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-Isobutoxy-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-Isobutoxy-1H-indole-2-carboxylic acid{1-[2-((1R,3S,5S)-3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-ethyl]-piperidin-4-yl}-amide4-Isobutoxy-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-Isobutoxy-1H-indole-2-carboxylic acid[4-(2-azepan-1-yl-ethyl)-phenyl]amide 4-Isobutoxy-1H-indole-2-carboxylicacid (4-{[methyl-(tetrahydro-pyran-4-yl)-amino]-methyl}cyclohexyl)-amide4-Isobutoxy-1H-indole-2-carboxylic acid(4-{[methyl-(tetrahydro-pyran-4-yl)-amino]-methyl}-phenyl)-amide4-Isobutoxy-1H-indole-2-carboxylic acid(4-{(R)-1-[methyl-(tetrahydro-pyran-4-yl)-amino]-ethyl}-phenyl)-amide4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]amide4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid{1-[2-(3-(R)-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid{1-[2-((1R,3S,5S)-3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-ethyl]-piperidin-4-yl}-amide4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-(3-Methyl-butyloxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride 4-Cyclopentylmethoxy-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(1,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide4-(2,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide4-(4-Methyl-pentyloxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride 4-(3,3-Dimethyl-butoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride 4-(Furan-2-ylmethoxy)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]piperidin-4-yl}-amide4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-Benzyloxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]amide4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amidedihydrochloride4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amidedihydrochloride4-(4-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride4-(4-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride 4-(Benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride 4-(Benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(Benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(Benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-(Benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-(6-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride4-(6-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride4-(6-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]piperidin-4-yl}-amidedihydrochloride4-(6-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amidedihydrochloride4-(6-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-(5-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide4-(5-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride4-(5-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-((3R,4R,5S)-4-hydroxy-3,5-dimethyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride4-(5-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amidedihydrochloride4-(5-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-(7-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride4-(4,6-Difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride4-(4,6-Difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride4-(4,6-Difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride4-(4,6-Difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amidedihydrochloride4-(4,6-Difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amidedihydrochloride4-(7-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride4-(6-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride4-(6-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(6-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(6-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amidedihydrochloride4-(4-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride4-(4-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride4-(4-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-((3R,4R,5S)-4-hydroxy-3,5-dimethyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride4-(4-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-(7-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride4-(7-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid[1-(2-piperidin-1-yl-ethyl)-piperidin-4-yl]-amide4-(7-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride4-(7-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride4-(7-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amidedihydrochloride4-(7-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-(6-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide4-(6-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide4-(6-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(6-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride4-(6-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-(6-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-(5-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide4-(5-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(4-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide4-(4-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(4-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(4-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-(4-Methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-(4,6-dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride4-(4,6-Dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(4,6-Dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride4-(4,6-Dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-(4,6-Dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-(5,6-dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amidedihydrochloride4-(5,6-Dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(5,6-Dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amidedihydrochloride4-(5,6-Dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amidedihydrochloride4-(5,6-Dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amidedihydrochloride 4-(4-Ethoxy-phenyl)-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-(4-Methoxy-phenyl)-1H-indole-2-carboxylic acid{1-[(S)-2-(4-hydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-Phenoxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]amide4-m-Tolyloxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]amide4-m-Tolyloxy-1H-indole-2-carboxylic acid{1-[2-(3-(RS)-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-m-Tolyloxy-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-p-Tolyloxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]amide4-p-Tolyloxy-1H-indole-2-carboxylic acid{1-[2-(3-(RS)-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-p-Tolyloxy-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(3-Fluoro-phenoxy)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)piperidin-4-yl]amide4-(3-Fluoro-phenoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(4-Fluoro-phenoxy)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)piperidin-4-yl]amide4-(4-Fluoro-phenoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(3,4-Difluoro-phenoxy)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide4-(3,5-Difluoro-phenoxy)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide4-(3,5-Difluoro-phenoxy)-1H-indole-2-carboxylic acid{1-[2-(3-RS-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(3,5-Difluoro-phenoxy)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(6-Chloro-pyridin-2-yloxy)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide4-Isobutoxy-1H-indole-2-carboxylic acid[1-(octahydro-quinolizin-1-yl)methyl)-piperidin-4-yl]-amidedihydrochloride 4-Isobutoxy-1H-indole-2-carboxylic acid[1-(1-methyl-piperidin-3-yl)methyl)-piperidin-4-yl]amide4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid{1-[(S)-2-((3R,4R)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4R,55)-3,4-dihydroxy-5-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid{1-[(R)-3-hydroxy-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-((3R,4R)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]piperidin-4-yl}-amide4-(2-Methyl-thiazol-4-ylmethoxy)-1H-indole-2-carboxylic acid[1-(octahydro-quinolizin-1-yl)methyl)-piperidin-4-yl]-amide4-(Benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[2-(3,4-dihydroxy-5-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-(5-Fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-((3RS,4SR)-3,4-dihydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(S)-2-((3RS,4SR)-3,4-dihydroxy-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(9S,9aS)-1-(octahydro-pyrido[2,1-c][1,4]oxazin-9-yl)methyl]-piperidin-4-yl}-amide4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{1-[(8S,8aS)-1-(hexahydro-pyrrolo[2,1-c][1,4]oxazin-8-yl)methyl]-piperidin-4-yl}-amide4-(4-Methoxy-phenyl)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide4-(4-Ethoxy-phenyl)-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acid{1-[(S)-2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-propyl]-piperidin-4-yl}-amide4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acid{1-[2-((3S,4S)-4-hydroxy-3-methyl-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-p-Tolyloxy-1H-indole-2-carboxylic acid{1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-yl}-amide4-Isobutoxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-1S-methyl-ethyl)-piperidin-4-yl]-amide4-Isobutoxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-1R-methyl-ethyl)-piperidin-4-yl]-amide4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid[1-(2S-azepan-1-yl-propyl)-piperidin-4-yl]-amide4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid[1-(2R-azepan-1-yl-propyl)-piperidin-4-yl]-amide4-Isobutoxy-1H-indole-2-carboxylic acid{1-[2-(3,6-dihydro-2H-pyridin-1-yl)-ethyl]-piperidin-4-yl}-amide4-Isobutoxy-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-azepan-1-yl)-ethyl]-piperidin-4-yl}-amide4-Isobutoxy-1H-indole-2-carboxylic acid{1-[2-(3-amino-azepan-1-yl)-ethyl]-piperidin-4-yl}-amide4-Isobutoxy-1H-indole-2-carboxylic acid{1-[2-(3-fluoro-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid[4-(2-piperidin-1-yl-ethyl)-phenyl]-amide4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid{4-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-phenyl}-amide4-Phenyl-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)piperidin-4-yl]amide4-(4-Trifluoromethyl-phenyl)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide4-p-Tolyl-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]amide4-(4-Dimethylamino-phenyl)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide4-Benzo[1,2,5]oxadiazol-5-yl-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide4-(4-Methoxy-phenyl)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]amide4-(3-Cyano-phenyl)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)piperidin-4-yl]amide4-(4-Ethoxy-phenyl)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)piperidin-4-yl]amide4-[3-(3-Methoxy-propoxy)-phenyl]-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide4-(4-Trifluoromethoxy-phenyl)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide4-(2,4-Dimethoxy-phenyl)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide4-(3,4-Dimethoxy-phenyl)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide4-Benzo[1,3]dioxol-5-yl-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide4-Pyridin-4-yl-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)piperidin-4-yl]amide4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]-amide4-(4-Ethoxy-phenyl)-1H-indole-2-carboxylic acid[1-(2-piperidin-1-yl-ethyl)-piperidin-4-yl]amide4-(4-Methoxy-phenyl)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(4-Ethoxy-phenyl)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acid{1-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-piperidin-4-yl}-amide4-(4-Methoxy-phenyl)-1H-indole-2-carboxylic acid{1-[2-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-ethyl]piperidin-4-yl}-amide4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acid{1-[2-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-ethyl]-piperidin-4-yl}-amide4-Hydroxy-1H-indole-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)piperidin-4-yl]amide4-Methoxy-benzo[b]thiophene-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]amide4-Isobutoxy-benzo[b]thiophene-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)-piperidin-4-yl]amide4-Isobutoxy-benzo[b]thiophene-2-carboxylic acid[1-(2-piperidin-1-yl-ethyl)-piperidin-4-yl]-amide and4-Methoxy-benzofuran-2-carboxylic acid[1-(2-azepan-1-yl-ethyl)piperidin-4-yl]amide. 4-5. (canceled)
 6. Aprocess for the preparation of a compound of formula (I) comprising: (a)reacting a compound of formula (III):

wherein R″ is H or a lower alkyl group, with a compound of formulaNH₂—X-Q-Y, the groups R, R9, Z, X, Q and Y being as defined in claim 1;or (b) for the preparation of compounds of formula (I) wherein X ispiperidin-4-yl and Q is —CH₂—CH₂—, and Y is a group having the formula—NR₇R₈ wherein N, R₇ and R₈ are linked to define collectively aheterocycloalkyl, bridged cycloalkyl, bridged heterocycloalkyl,heteroaryl, or fused aryl-heterocycloalkyl, reacting a compound offormula (IV):

with a compound of formula NHR₇R₈, wherein R₇ and R₈ are as definedabove, and R, R₉ and Z are as defined earlier; or (c) for thepreparation of compounds of formula (I) wherein X is piperidin-4-yl andQ is CH₂—, reacting a compound of formula (V):

in which R, R9 and Z are as defined above, with a compound of formulaHO—CH₂—Y, in which Y is as defined earlier; or (d) for the preparationof compounds of formula (I) wherein R is an optionally substituted arylgroup, appropriately substituting the Br group in a compound of formula(VI) for said substituted aryl group:

wherein Z, R9, X, Q and Y are as earlier defined; and recovering theresultant compounds of formula (I) in free or salt form.
 7. A compoundobtainable by the process of claim
 6. 8. A pharmaceutical compositioncomprising a compound according to claim 1 in association with apharmaceutically acceptable diluent or carrier. 9-10. (canceled)
 11. Amethod of inhibiting chemokine receptors or macrophage protein or ofreducing inflammation in a subject in need of such treatment, whichmethod comprises administering to said subject an effective amount of acompound according to claim
 1. 12. A method of treating an inflammatoryor autoimmune disease or condition, comprising administering to saidsubject an effective amount of a compound according to claim
 1. 13. Amethod of treating HIV infection or AIDS, comprising administering tosaid subject an effective amount of a compound according to claim
 1. 14.A method of treating an inflammatory or autoimmune disease or conditionor HIV or AIDS, comprising administering to a subject in need thereof,an effective amount of a compound according to claim 1, or apharmaceutically acceptable salt thereof, in combination with one ormore agents selected from: methotrexate, an anti-TNF agent, an anti-IL-1agent, a nucleoside or non-nucleoside reverse transcriptase inhibitor,an HIV protease inhibitor, fusion inhibitor and antiretroviral agent.